Secreted/cell bound poxvirus proteins and methods of use thereof as vaccines and anti-viral agents

ABSTRACT

Compositions and methods for the treatment and prevention of pox virus infections are disclosed.

This application is a continuation-in-part of PCT/US08/84929 filed Nov. 26, 2008 which in turn claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application 60/990,151 filed Nov. 26, 2007, the entire disclosure of each being incorporated by reference herein.

Pursuant to 35 U.S.C. §202(c) it is acknowledged that the U.S. Government has rights in the invention described, which was made in part with funds from the National Institutes of Health, Grant Number RO1A1065544.

FIELD OF THE INVENTION

This invention relates to the fields of drug discovery and vaccine production. More specifically, the invention provides materials and methods for developing effective anti-viral agents.

BACKGROUND OF THE INVENTION

Several publications and patent documents are cited throughout the specification in order to describe the state of the art to which this invention pertains. Each of these citations is incorporated by reference herein as though set forth in full.

The poxviridae comprise a large family of complex DNA viruses that replicate in the cytoplasm of vertebrate and invertebrate cells. In humans, smallpox was by far the most important poxvirus infection. The causative agent of smallpox is the variola virus, a member of the genus Orthopoxvirus. Vaccinia virus, also a member of the genus Orthopoxvirus in the family of Poxviridae, was used as live vaccine to immunize against smallpox. Successful worldwide vaccination with Vaccinia virus culminated in the eradication of variola virus (The global eradication of smallpox. Final report of the global commission for the certification of smallpox eradication; History of Public Health, No. 4, Geneva: World Health Organization, 1980). However, smallpox or smallpoxlike diseases still pose a major potential health problem. Additionally, certain pox virus infections cause great damage to livestock and wild life populations and are often require costly eradication procedures.

By inducing an anti-viral state in cells (1) and modulating the immune response (2), IFNs are major mediators of the anti-viral defense (3). Thus, the interferon (IFN) pathway is one of the most frequent targets of immune response modifiers (IRMs) encoded by viruses (1, 4) including OPVs (5). Type I IFN-α and -β signal through a common receptor (IFN-α/βR) which is expressed at the surface of the majority of cells (6). Most OPVs encode a high affinity type I IFN binding protein (bp) supposed to inhibit type I IFN signaling by sequestering Type I IFNs away from the IFN-α/βR (7-11). In the case of ECTV, the Type I IFN by is encoded in gene EVM166 and binds with high affinity to mouse IFN-α but, surprisingly, not-β (7) (herein eIFN-α bp). While it is presumed that IRMs are important for OPV virulence, only a few studies have been performed in vivo with OPVs in their natural hosts. Studying the role of IRMs in natural hosts is essential to understand virus virulence, define new targets of anti-viral therapies, and test the possibility of using secreted IRMs as targets of subunit anti-viral vaccines.

SUMMARY OF THE INVENTION

In accordance with the present invention, an anti-pox vaccine is provided. An exemplary vaccine comprises a SPVP in a biologically compatible medium, which upon administration to a patient, induces an immune response which is effective in attenuating pox virus infection. The vaccine may optionally comprise a pharmaceutical adjuvant.

Suitable SPVP for use as immunogens include, without limitation, viral interferon binding proteins, viral c-type lectins, viral chemokines, viral complement binding proteins, viral interleukin-1 receptor binding proteins, viral interleukin-18 binding proteins, viral interferon gamma receptor binding proteins, viral interferon α/β receptor binding proteins, viral semaphorins and viral TNF receptor binding proteins. The sequences encoding the SPVPs of the invention and their cognate pox viruses are provided in Tables I-XI. In a particularly preferred embodiment, the SPVP is an interferon a binding protein and is listed in table IX.

Also encompassed by the present invention are methods for inhibiting infection with a pox virus that expresses a SPVP. An exemplary method entails administering an SPVP containing vaccine as described above which is effective to attenuate pox infection in the subject.

In an alternative embodiment, methods for prevention and/or treatment of a pox virus infection comprising passive infusion of neutralizing anti-pox virus antibodies or functional fragments thereof are also disclosed. Such functional fragments can include a single chain Fv antibody molecule, a diabody, a tribody, a tetrabody, a recombinantly produced IgG, Fab, Fab′, F(ab′)₂, F(v), scFv, scFv₂, scFv-Fc, minibody, a bispecific antibody, an Affibody®, and a peptabody. In a preferred embodiment of this aspect of the invention, the antibodies block the action of a virally encoded immune response modifier protein. In a particularly preferred embodiment the antibody blocks the action of an interferon binding protein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. Generation of Δ166 and Rev166. FIG. 1 a, FIG. 1 b) Schematic representation of the strategies to generate Δ166 and Rev166 (not to scale) FIG. 1 a) A construct consisting of EGFP (green) controlled by the early/late4 7.5 OPV promoter (yellow) and flanked by the 5′ and 3′ 300 by of EVM166 (dark blue) was introduced into plasmid Bluescript II KS+ (orange). This targeting vector was used to generate Δ166 by homologous recombination with WT ECTV as indicated. Recombinant plaques were selected by green fluorescence. The correct insertion of EGFP was determined by sequencing using oligos (arrows) corresponding to ECTV sequences flanking EVM166 (light blue). FIG. 1 b) As in a) but the process was reversed and non-fluorescent plaques were selected to obtain Rev166. FIG. 1 c) Micrograph of WT and Δ166 plaques showing the fluorescence of Δ166.

FIG. 2. eIFN-α bp is essential for ECTV virulence. FIG. 2 a) Mouse fibrosarcoma A9 cells were infected with 0.01 PFU/cell of the indicated viruses. Cell associated and free virus was determined at the indicated times after infection. Data points are means±SD of three replicate wells. FIG. 2 b) Balb/c mice were infected with 300 PFU of the indicated viruses. Virus titers in the infected footpad and spleen were determined at the indicated times. Data points are means±SD of three mice. FIG. 2 c) Balb/c mice were infected in the footpad with 300 PFU of the indicated viruses. Mice were observed for survival. Data corresponds to five mice/group.

FIG. 3. Enlarged lymphoid organs and reduced liver pathology in Balb/c mice infected with D166. Mice were infected with the indicated viruses and organs harvested and photographed seven days PI.

FIG. 4. eIFN-α bp affects adaptive and innate immunity. FIG. 4 a) Mice were infected with the indicated viruses. Five days PI, anti-ECTV CD8⁺ T cell responses were determined in the popliteal draining lymph node (D-LN). Plots are gated on CD8⁺ cells. Data corresponds to a pool of three LN and is representative of three similar experiments. FIG. 4 b) RAG-1 KO mice were infected with the indicated viruses and observed for survival. Data corresponds to five mice/group. FIG. 4 c) Balb/c mice were infected with the indicated viruses. Three days PI, cells from the D-LN and contralateral non-draining lymph node (ND-LN) were stained as indicated. Data corresponds to a pool of three LNs and is representative of two experiments. FIG. 4 d) RAG-1 KO mice depleted of NK cells using anti-Asialo-GM1 antibody were infected with the indicated viruses and observed for survival. Data corresponds to five mice/group.

FIG. 5. eIFN-α bp is a natural target of the antibody response. FIG. 5 a) Sera from mice infected with the indicated viruses was tested for anti-ECTV antibodies in ELISA using virus particles (infected cell lysates) as antigen. FIG. 5 b) Wells of ELISA plates were covered with 200 IU of recombinant mouse IFN-α and treated with the following reagents in that order: the indicated amounts of Rec eIFN-α bp, sera from mice immune to ECTV Δ166 or Rev 166 as indicated, peroxidase labelled goat anti-mouse IgG, and TMB substrate. FIG. 5 c) MEFs were incubated with the indicated amounts of IFN-α or -β for 24 h in the presence or in the absence of the indicated amounts of Rec eIFN-α bp. MEF were next infected with VSV and after additional 24 h, fixed and stained with 1% crystal violet. FIG. 5 e) Mice were inoculated i.v. with 50 μg Rec eIFN-α bp immediately and 3 days PI with ECTV Δ166. A group of control infected mice received PBS instead of Rec eIFN-α bp while a second control group received Rec eIFN-α bp but remained uninfected. Survival was monitored. FIG. 5 d) As in (a) but using Rec eIFN-α bp as antigen. FIG. 5f) MEFs were treated for 24 hours with 20 IU IFN-α in the presence or the absence of the indicated amounts of Rec eIFN-α bp and/or sera from ECTV Δ166 or Rev166 immune mice. MEFs were next infected with VSV, incubated for 24 hours and then fixed and stained with crystal violet.

FIG. 6. Immunization with Rec eIFN-α bp protects from mousepox. FIG. 6 a) Balb/c mice were immunized and boosted twice with Rec eIFN-α bp or control recombinant human HER2/neu produced in E. coli. As additional controls, Balb/c mice were infected with Δ166 and B6 mice with Rev166. Three weeks after the last boost or infection, sera was collected and anti-eIFN-Δ by was determined by ELISA. FIG. 6 b) The immunized mice in a were challenged with 300 PFU WT ECTV and survival was monitored. Data corresponds to 5 mice/group and is representative of 3 identical experiments.

FIG. 7. Rabbit anti-IFN-α bp sera protects from mousepox pre- and post-exposure. BALB/c mice were infected with 3,000 PFU ECTV in the footpad, treated as indicated and survival monitored.

FIG. 8. Characterization of MB-mAb and MNB-mAb. Mabs were produced by fusing the splenocytes from mice immunized with recombinant T1-IFNbp-ECTV with SP2cells. Hybridomas producing anti-T1-IFNbp mAbs were selected using an ELISA assay. A) Identification of MB-mAb and MNB-mAb: MB- and MNB-mAb were identified in a biological assay where L cells were treated as indicated followed by infection with vesicular stomatits virus (VSV) expressing GFP. The cells were observed at the microscope 24 hours later. Results were as follows: Column 1: With no treatment, many cells were infected by the virus (many green cells). Column 2: Addition of IFNα prevented infection (no green cells). Column 3: Addition of recombinant T1-IFNbp-ECTV neutralized the activity of IFNα and the cells became infected again (many green cells). Column 4: Addition of MB-mAb prevented T1-IFNbp-ECTV from blocking IFNα (no green cells). Column 5: Addition of MNB-mAb did not prevent T1-IFNbp-ECTV from blocking IFNα. B) Both MB-mAb and MNB-mAb stain infected and uninfected cells in mixed cultures as the IFNbp will be elaborated from infected cells and bind to membranes of neighboring uninfected cells. L cells were infected with 0.1 PFU ECTV-GFP or ECTV-Δ166-GFP. The next day, the cells were stained with MB-mAb or MNB-mAb followed by anti-mouse Alexa647 and analyzed by FACS. In cultures infected with ECTV-GFP (left panels), both infected (GFP+, right quadrants) and uninfected cells (GFP−, left quadrants) were stained by both mAbs (all the cells were in the upper quadrants, T1-IFNbp+). As expected, when cultures were infected with the virus that lacks the T1-IFNbp (right panels), infected (GFP+, right quadrants) and uninfected cells (GFP−, left quadrants) did not stain with anti-T1-IFNbp (all cells in the lower quadrants, T1-IFNbp-). C) MB-mAb recognizes T1-IFN-bp-MPXV: Hela cells were incubated for 1 hour with recombinant EVM135 as a negative control (redlines/curves to the left in each panel), or, as indicated, with recombinant T1-IFNbp-VARV, supernatant of MPXV infected cells, supernatant of VACV infected cells, or recombinant T1-IFNbp-ECTV (blue lines/curves to the right in each panel). Cells were washed, incubated with MB-mAb, followed by anti-mouse IgG-FITC and analyzed by FACS. D) MB-mAb blocks the biological activity of T1-IFNbp-VARV. Hela cells were treated as indicated. Column 1: when cells were infected with VSV they were killed. Column 2: IFNα treatment did not affect the survival of uninfected cells. Column 3: IFNα protected cells from VSV. Column 4: T1-IFNbp-VARV neutralized the protective effects of IFNα. Column 5: MB-mAb blocked the T1-IFNbp-VARV restoring the protective effects of IFNα (not all the wells were adjacent as depicted). Identical results were obtained with supernatants from MPXV infected cells.

FIG. 9. MB-mAb treatment restores T1-IFN signaling in the liver and protects from lethal mouse pox late after infection. A) Mice were infected with 3,000 PFU ECTV-Luc or left uninfected. Five days post infection (dpi), mice were treated with the indicated mAbs and transcripts of the indicated genes were determined by qPCR one dpi. Indicated genes are as follows in descending order: “MX1” (myxovirus resistance 1), “IRF 7” (interferon regulatory factor 7), “IFNa2” (interferon alpha 2). B) Mice were infected with 3,000 PFU ECTV-Luc. Five dpi, mice were treated with the indicated mAbs. One or two dpt, the mice were sacrificed and virus loads in the liver were determined by Luc activity. C) Mice were infected with 3,000 PFU ECTV-Luc. Five dpi, mice were treated with the indicated mAbs. Two days post treatment (dpt), the livers were collected and sections stained by H & E. D) As in B), but analyzed two dpt the mice were inoculated IP with luciferase substrate, anesthetized and analyzed by whole body imaging using a Carestream in vivo imaging system (Rochester, N.Y.). Luciferase activity scale is on the right side of the figure. E) Mice were infected with WT-ECTV and treated as indicated 5 dpi. Survival was monitored. Statistics: Isotype control vs. MNB-mAb, P=0.4; Isotype Control vs. MN-mAb P=0.0006; MNB-mAb vs. MB-mAb, P=0.005 by Log-rank Mantel-Cox test.

DETAILED DESCRIPTION OF THE INVENTION

Non-living anti-viral vaccines traditionally target proteins expressed at the surface of the virion with the hope of preventing infection through neutralizing antibodies. Orthopoxviruses (OPVs) including variola virus (V ARV, agent of smallpox) and the murine equivalent ectromelia virus (ECTV, agent of mousepox) encode immune response modifiers (IRMs) thought to increase virulence by decreasing the host immune response. Here we show that one of these IRMs, the interferon alpha binding protein of ECTV (eIFN-α bp), is absolutely essential for ECTV virulence and is a natural target of the antibody response. Strikingly, we demonstrate that immunization with recombinant eIFN-α bp protects mice from lethal mousepox. Together, this work has important implications for our understanding of the role of type I IFNs in OPV infections, the role of IRMs in OPV virulence, and the mechanisms whereby the smallpox vaccine protects. Furthermore, these experiments provide a rationale for the use of virulence factors as targets of antiviral vaccines.

While attenuation of mouse pox infection is described herein, this approach may be extrapolated to immunize humans and animals against other pox virus infections. As mentioned above, each pox virus expresses SPVP which could be employed as a target to induce viral immunity or resistance. Tables I-XI provide a listing of ortholog genes from many poxviruses that are secreted virulence factors and thus may be employed in the methods described herein. The function of the factor is indicated in the title and names of the virus and gene number are also provided. For example, other such SPVP include without limitation, CC-lectin like, CD47-like, complement-binding, Il-1β receptor, Il-18 binding protein, interferon gamma receptor, interferon beta receptor, semaphorin, and TNF receptor. See Tables I-XI.

Definitions

The term “SPVP” as used herein refers to a non-structural, secreted viral proteins that may or may not bind to the surface of cells during active infection. SPVP are frequently immune response modifiers and often contribute to viral virulence.

As defined herein, the term “attenuated” means a virus which is immunologically related to the wild type pox virus (i.e., the virulent virus) but which is not itself pathogenic and does not produce a “classical pox disease,” and is not a wild type virus. An attenuated measles virus is replication-competent, in that it is capable of infecting and replicating in a host cell without additional viral functions supplied by, for example, a helper virus or a plasmid expression construct encoding such additional functions. When referring to viral infection in a subject, “attenuate” means inhibition of infection or decreasing viral load in the subject.

As used herein, the terms “wild-type” or “wild-type virus” refer to the characteristics of a pox virus as it is found in nature which is pathogenic.

As used herein, the term “patient” or “subject” refers to an organism to which viruses of the invention can be administered. Preferably, a patient is a bird or a mammal, e.g., a human, primate, livestock animal, or a rodent.

As used herein, the term “biological fluid” refers to any extracellular bodily fluid, including but not limited to blood, urine, saliva, interstitial fluid, lymph, and cerebrospinal fluid.

An “immune response” signifies any reaction produced by an antigen, such as a viral antigen, in a host having a functioning immune system. Immune responses may be either humoral in nature, that is, involve production of immunoglobulins or antibodies, or cellular in nature, involving various types of B and T lymphocytes, dendritic cells, macrophages, antigen presenting cells and the like, or both. Immune responses may also involve the production or elaboration of various effector molecules such as cytokines, lymphokines and the like. Immune responses may be measured both in in vitro and in various cellular or animal systems. Such immune responses may be important in protecting the host from disease and may be used prophylactically and therapeutically.

An “antibody” or “antibody molecule” is any immunoglobulin, including antibodies and fragments thereof, that binds to a specific antigen. The term includes polyclonal, monoclonal, chimeric, single domain (Dab) and bispecific antibodies. As used herein, antibody or antibody molecule contemplates recombinantly generated intact immunoglobulin molecules and immunologically active portions of an immunoglobulin molecule such as, without limitation: Fab, Fab′, F(ab′)₂, F(v), scFv, scFv₂, scFv-Fc, minibody, diabody, tetrabody, single variable domain (e.g., variable heavy domain, variable light domain), bispecific, Affibody® molecules (Affibody, Bromma, Sweden), and peptabodies (Terskikh et al. (1997) PNAS 94:1663-1668). Dabs can be composed of a single variable light or heavy chain domain. In a certain embodiment of the invention, the variable light domain and/or variable heavy domain specific for an immune response modifier protein are inserted into the backbone of the above mentioned antibody constructs. Methods for recombinantly producing antibodies are well-known in the art. For example, commercial vectors comprising constant genes to make IgGs from scFvs are provided by Lonza Biologics (Slough, United Kingdom).

“Fv” is an antibody fragment which contains an antigen-recognition and -binding site. This region consists of a dimer of one heavy- and one light-chain variable domain in tight, non-covalent association. It is in this configuration that the three CDRs of each variable domain interact to define an antigen-binding site on the surface of the V_(H)-V_(L) dimer. Collectively, the six CDRs confer antigen-binding specificity to the antibody. However, even a single variable domain (or half of an Fv comprising only three CDRs specific for an antigen) has the ability to recognize and bind antigen, although often at a lower affinity than the entire binding site.

“Single-chain Fv” or “scFv” antibody fragments comprise the V_(H) and V_(L) domains of an antibody, wherein these domains are present in a single polypeptide chain. Generally, the Fv polypeptide further comprises a polypeptide linker between the V_(H) and V_(L) domains which enables the scFv to form the desired structure for antigen binding. For a review of scFv see, for example, Pluckthun, A. in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., Springer-Verlag, New York, pp. 269-315 (1994).

The term “diabodies” refers to small antibody fragments with two antigen-binding sites, which fragments comprise a heavy-chain variable domain (V_(H)) connected to a light-chain variable domain (V_(L)) on the same polypeptide chain (V_(H)-V_(L)). By using a linker that is too short to allow pairing between the two domains on the same chain, the domains are forced to pair with the complementary domains of another chain and create two antigen-binding sites. Diabodies are described more fully in, for example, EP 404,097; WO 93/11161; and Holliger et al., (1993) Proc. Natl. Acad. Sci. USA, 90: 6444-6448.

With respect to antibodies, the term “immunologically specific” refers to antibodies that bind to one or more epitopes of a protein or compound of interest, but which do not substantially recognize and bind other molecules in a sample containing a mixed population of antigenic biological molecules.

As used herein, the term “administering systemically” refers to exposure of the cells of an organism to an attenuated pox virus via the circulatory system of the patient, such as by intravenous injection or the use of a medical access device, such as a catheter.

As used herein, the term “recombinant virus” or “modified virus” refers to a virus or viral polypeptide which is altered by genetic engineering, by modification or manipulation of the genetic material encoding that polypeptide, or found in the virus such that it is not identical to the naturally occurring virus or polypeptide.

According to the methods of the subject invention, the anti-pox vaccine compositions described herein are administered to susceptible hosts, in an effective amount and manner to induce protective immunity against subsequent challenge or infection of the host by the cognate pox virus. The vaccines, comprising SPVP or attenuated virus, are typically administered parenterally, by injection, for example, either subcutaneously, intraperitoneally, or intramuscularly. Other suitable modes of administration include oral or nasal administration. Usually, the vaccines are administered to a host at least two times, with an interval of one or more weeks between each administration. However, other regimens for the initial and booster administrations of the vaccine are contemplated, and may depend on the judgment of the practitioner and the particular host animal being treated.

In an alternative embodiment, the anti-pox vaccine is administered to the patient in a biologically compatible solution or a pharmaceutically acceptable delivery vehicle, by administration either directly into cells or systemically (e.g., intravenously). Suitable pharmaceutical formulations, in part, depend upon the use or the route of entry, for example transdermal, or by injection. Such forms should not prevent the composition or formulation from reaching a target cell (i.e., a cell to which the virus is desired to be delivered to) or exerting its effect. For example, pharmacological compositions injected into the blood stream should be soluble. The anti-pox vaccines described herein may optionally also contain a viral structural protein preparation to facilitate the mounting of a robust immune response. Suitable proteins for this purpose, include, without limitation, A33R, B5R and L1R from vaccinia and orthologs thereof present in other poxviruses.

While dosages administered will vary from patient to patient (e.g., depending upon the size of the patient), a “therapeutically effective dose” will be determined by setting as a lower limit, the concentration of virus proven to be safe as a vaccine (e.g., 10³ pfu) and escalating to higher doses of up to 10¹² pfu, while monitoring for a reduction in viral load along with the presence of any deleterious side effects. Escalating dose studies are routine in the art (see, e.g., Nies and Spielberg, “Principles of Therapeutics,” In Goodman & Gilman's The Pharmacological Basis of Therapeutics, eds. Hardman, et al., McGraw-Hill, NY, 1996, pp 43 62).

In a preferred embodiment, SPVP will be infused into the patient in a biologically compatible medium. Thus, the SPVP is delivered systemically via injection in an amount effective to generate an antibody response to the molecule. Alternatively, an intravenous delivery device designed for administration of multiple doses of a medicament may be employed for this purpose. Such devices include, but are not limited to, winged infusion needles, peripheral intravenous catheters, midline catheters, peripherally inserted central catheters (PICC), and surgically placed catheters or ports (see, e.g., U.S. Pat. No. 6,012,034).

In preferred embodiments of the invention, a composition comprising an attenuated pox virus is delivered in a therapeutically effective dose in the range of from about 10³ pfu to about 10¹² pfu. In one embodiment of the invention, the dose range is 10⁵ to 10⁷ pfu. In some embodiments, the therapeutically effective dose is provided in repeated doses. Repeat doses (using the same, or further modified virus) can be administered by the same route as initially used or by another route. A therapeutically effective dose can be delivered in several discrete doses (e.g., days or weeks apart) and in one embodiment of the invention, one to about twelve doses are provided. Alternatively, a therapeutically effective dose of attenuated pox virus is delivered by a sustained release formulation.

The vaccine compositions of the subject invention can be prepared by procedures well known in the art. For example, the vaccines are typically prepared as injectables, e.g., liquid solutions or suspensions for subcutaneous administration. The vaccines are administered in a manner that is compatible with dosage formulation, and in such amount as will be therapeutically effective and immunogenic in the recipient. The optimal dosages and administration patterns for a particular vaccine formulation can be readily determined by a person skilled in the art.

SPVP or attenuated viruses are typically combined with an adjuvant just prior to administration. Adjuvants used in the vaccine formulations typically were either threonyl muramyl dipeptide (MDP) (Byars et al., 1987) or a combination of Freund's complete and incomplete adjuvants. A variety of other adjuvants suitable for use with the methods and vaccines of the subject invention, such as alum, are well known in the art and are contemplated for use with the subject invention.

Finally, as demonstrated herein, neutralizing anti-SPVP antibodies can be generated for passive infusion into a patient. In this embodiment, antibodies which neutralize the pox virus are produced in large quantities and an effective amount of the same infused into the subject to be treated to prevent or treat pox virus infections. Methods for passive infusion of antibodies into human patients are well known to the skilled clinician. The passive transfer of antibodies in the form of whole plasma or fractionated preparations, such as gammaglobulins, has been used for both the prophylaxis and treatment of infection in patients with primary immunodeficiency, as well as infections associated with transplantation, chronic leukemia, premature birth, and surgery (See Berkman, S A, et al., Ann. Intern. Med. 112:278, 1990; Ziegler, E J, et al., New England J. of Med. 307;1225, 1982; Gordon, D S, Am. J. Med. 83:1m 1987, [suppl. 4A]; Winston, D J, et al., Ann. Intern. Med. 106:12, 1987; The National Institute of Child Health and Human Development Intravenous Immunoglobulin Study Group, New England J. of Med. 325:73, 1991). Hyperimmune antibodies directed against a single organism passively transferred to recipients has been particularly useful in the treatment of cytomegalovirus, hepatitis B, tetanus, vaccinia, and herpes (Orenstein, W A, et al., J. Pedicat. 98:368, 1981; Snydman, D R, et al., New England J. of Med. 317:1049, 1987; Beasley, et al., Lancet 2:388, 1981). Accordingly, such treatment methods are encompassed by the present invention.

The following examples are provided to illustrate certain embodiments of the invention. They are not intended to limit the invention in any way.

EXAMPLE I

Most existing anti-viral recombinant vaccines are directed to target proteins that form part of the structure of the virus. Poxviruses encode proteins that are not part of the virus structure and are secreted into the extracellular milieu and sometimes bind to the surface of cells. Most of these proteins, referred to herein as SPVP, are immune response modifiers and involved in virus virulence. Accordingly, we hypothesized that if a SPVP were essential for virulence, anti-pox vaccines could be designed to induce antibodies to these essential proteins. The antibodies so produced should neutralize the function of the SPVP and prevent pox virus disease. To test this hypothesis we generated ectromelia virus (a poxvirus) deficient in the open reading frame of EVM166 (Δ166) that encodes for the SPVP interferon-alpha binding protein (IFN-α bp). Surprisingly, this deletion extremely attenuated the ability of the recombinant virus to infect mice. These data indicate that IFN-α binding protein is essential for poxvirus pathogenesis. We then produced recombinant IFN-α binding protein in E. coli and used this to immunize mice. We found that when immunized mice were infected with pathogenic ectromelia virus, they were protected from lethal disease. Thus, SPVP can serve as effective targets for anti-pox virus vaccines.

The following materials and methods are provided to facilitate the practice of the invention.

Mice: Balb/c mice were purchased from the National Cancer Institute (Frederick). RAG1-KO mice in a C57BL/6 background were originally purchased from Jackson laboratories and bred at FCCC. C57BL/6 mice were obtained from the FCCC colony. All mice were used in experiments when they were 5-8 weeks old. All protocols involving mice were approved by the FCCC Institutional Animal Use and Care Committee (IACUC).

Media and cells: were as previously described (12-15) except for mouse embryonic fibroblasts (MEF) that were prepared according to standard methods (37) from day 12-14 embryos and were maintained in DMEM containing 15% fetal bovine serum (FBS) and antibiotics.

Viruses and infections: Stocks of WT vaccinia virus (VACV) Western Reserve were produced in tissue culture as before (17, 21, 22, 26). Stocks of ectromelia virus (ECTV) were produced in A9 cells. For ECTV multi-step growth curves, BS-C-1 or A9 cells were infected with ECTV at an MOI of 0.01 for 1 hour. Unabsorbed virus was removed by washing the cells with PBS three times, and the cells were incubated at 37° C. 5% CO₂ in 3 ml of DMEM containing 2.5% FBS. At various times PI, supernatants and cells were harvested separately and virus titers were determined. All growth analyses were performed in triplicate. VACV and ECTV titers in stocks, tissues and cells were as before (17, 21, 22, 26). Vesicular Stomatitis Virus (VSV) Indiana strain was expanded in A9 cell and the viral yield was determined by a plaque assay on Vero cells. To generate Δ166, we used an adaptation of the method of homologous recombination (17). See FIG. 1. Briefly, a construct containing the 5′ 300 by of ECTV EVM166 the early/late OPV 7.5 promoter, the complete sequence of enhanced GFP (EGFP) and the 3′ 300 by of EVM166 in that order was cloned into plasmid Bluescript II SK+. This targeting vector was used to transfect mouse A9 cells using Lipofectamine 2000 as per manufacturer instructions (Invitrogen). The transfected cells were infected with wild type ECTV (Moscow strain, 0.3 pfu/cell) in 6 well plates. Two days later, transfected/infected A9 cells were harvested using a rubber policeman, frozen and thawed and different dilutions of cell lysates were used to infect BS-C-1 cells in 6 well plates. Two hours after infection, the cells were overlaid with media containing 0.5% agarose. Four days later, green-fluorescent plaques (FIG. 1 b) were picked with a pipette tip and used to infect a new set of cells. The purification procedure was performed 5 times until all plaques were fluorescent. The viral DNA from ≈300 by downstream and upstream of EVM 166 was amplified by PCR, cloned and sequenced. An isolate with the correct sequence was expanded for subsequent experiments with the same methods as for WT virus. To generate Rev166, a procedure similar to that for Δ166 was used but the targeting vector contained the whole coding sequence of EVM166 and the target virus was Δ166. Non-fluorescent plaques were amplified (FIG. 1 c). For mouse infections with ECTV, mice were inoculated with 300 PFU of the various ECTV in the left hind footpad in 50 μl PBS. It should be noted that in the past (26), we have used Balb/c mice from the FCCC stock where 20-40% survival was frequently observed with 3,000 PFU ECTV WT while the LD50 that we recently determined for Balb/c mice from NCI (and also from Jackson Laboratories) is ˜0.1 PFU. The reason for this difference in susceptibility to lethal mousepox in Balb/c mice from different origins is unknown. Mice were monitored for signs of mousepox and death as described previously (17, 21, 22, 26). VACV infection was performed as before (17, 21, 22, 26). For NK cell depletions, mice were inoculated intraperitoneally with 10 μl of anti-Asialo GM1 antibody (Wako Pure Chemical Industries, Ltd.) 1 day before viral infection.

Flow cytometry: Performed as described previously (17, 21, 22, 26).

Production and use of Rec eIFN-α bp: The coding sequence for eIFN-α bp without the signal peptide (residues 1-31) was amplified by PCR from viral DNA and inserted into vector pET28 (Novagen) with a C-terminal His tag. Expression and refolding of Rec eIFN-α bp was as previously described for EVM135 (26) except that removal of urea was performed by serial dialysis overnight against 6, 4, 2, 1 and finally 0 M urea. To determine Abs to eIFN-α bp in sera from infected or immunized mice, 96-well bottom ELISA plates (Corning) were coated with 100 ng recombinant eIFN-α bp or lysates of VACV-infected cells (1×10⁷ PFU/ml) in 0.1 ml of PBS at 4° C. overnight. Plates were blocked for 2 h at 37° C. with PBS containing 1% BSA. Mice sera were serially diluted in PBS containing 0.5% BSA, 0.05% Tween 20, and 0.1 ml was added to each well. The plates were then incubated for 1 h at 37° C. and washed three times with PBST (PBS with 0.05% Tween 20). 0.1 ml of peroxidase-conjugated affinity purified goat anti-mouse IgG (γ chain specific, KPL) were added to each well at a dilution of 1: 2000, incubated for 0.5 h at 37° C., and then washed five times with PBST. 50 ul of SureBlue TMB 1-Component Microwell Peroxidase Substrate (KPL) was added to each well and the reaction stopped by addition of 0.1 ml 0.12 M HCl. The optical density (OD) at 450 nm was determined using a microplate spectrophotometer (μQuant, Bio-Tec). To determine binding of Rec eIFN-α bp to IFN-α, 96-well bottom ELISA plates were coated with 200 IU of recombinant mouse IFN-α and blocked as above. Serially diluted Rec eIFN-α bp protein or control EVM135 (26) in 0.1 ml of PBS were added to each well and incubated for 2 h at 37° C. After three washes with PBST, 0.1 ml of a 1/100 dilution in PBS of sera harvested from B6 mice infected three weeks previously with either Rev166 or Δ166 was added. The plates were incubated 0.5 hours at RT. This was followed by peroxidase-conjugated affinity purified goat anti-mouse IgG, substrate and optical density determination as above. To determine the biological activity of Rec eIFN-α bp in vitro, 2×10⁵ MEF were seeded into 24-well-plates. The following day, different amounts of Rec eIFN-α bp were added for 2 h at 37° C. in 0.5 ml DMEM 10% FBS followed by the addition of the indicated amounts of mouse IFN-α or IFN-β. After overnight incubation, the cells were infected with 10⁸ PFU/well VSV in 0.5 ml of DMEM 2.5% FBS. After one hour incubation, the media was replaced with 1 ml of complete DMEM 10% FBS and the cells were incubated overnight. The cells were washed twice with PBS and the MEF monolayer was visualized by fixing with methanol and staining with 1% of crystal violet. To determine neutralization of the biological activity of Rec eIFN-α bp with immune sera, the assay was performed as above but the indicated amounts of heat-inactivated (56° C. 30 min) sera from infected (three weeks PI) or immunized (see below) mice were added to MEF in 0.5 ml DMEM 10 1 h before the addition of Rec eIFN-α bp. To determine the biological activity of Rec eIFN-α bp in vivo, mice were inoculated i.v. with 50 μg Rec IFN-α bp in 0.5 ml PBS immediately and 3 days PI with ECTV Δ166. A group of control infected mice received PBS instead of Rec eIFN-α bp while a second control group received Rec eIFN-α bp but remained uninfected. Mousepox and death was determined as previously described (17, 21, 22, 26). For immunizations, male Balb/c mice were immunized every other week, three times with 20 μg Rec eIFN-α bp or recombinant human HER2/neu emulsified in incomplete Freund's adjuvant (IFA). Both recombinant proteins were produced in E. coli. Three weeks after the last immunization, the mice were bled to determine Ab in serum and infected with WT ECTV two days later.

Statistics: Data was analyzed using Excel Analysis Tool Pack (Microsoft).

Results eIFN-α bp is Essential for ECTV Virulence

To elucidate the importance of the eIFN-α bp in ECTV virulence, we produced a mutant ECTV (Δ166) where EVM166 was replaced with enhanced green fluorescence protein (EGFP) (17) (FIG. 1 a). In addition, as a control for any defects that Δ166 may had acquired in other loci during cloning, we also generated a revertant virus (Rev166) where EVM166 was reintroduced to its original location in Δ166 (FIG. 1 b). In initial experiments to characterize the viruses we found that ECTV Δ166, Rev166 and WT produced similar amounts of infectious virus in multi-step growth curves as determined in mouse A9 cells (FIG. 2 a) and also in monkey BSC-1 cells (not shown). This indicated that eIFN-α bp was not required for replication in tissue culture and is consisted with expectations for a non-structural secreted protein that does not play a role in DNA replication or virus assembly.

The natural route of ECTV entry is through microabrasions of the footpad (18). Via this route, it first multiplies at the site of entry followed by spread to and replication in the local draining lymph node (D-LN). From there, ECTV follows the efferent lymphatic vessels to reach the blood and then visceral organs such as the liver and the spleen (18). In mousepox susceptible strains such as Balb/c, WT ECTV reaches very high titers in these organs. Thus, to determine whether eIFN-α bp is important for efficient replication and spread in vivo, we infected Balb/c mice in the footpad with 300 plaque forming units (PFU) of ECTV Δ166, Rev166 or WT. Three, five, and seven days post infection (PI), we quantified virus loads in the infected footpad to determine local replication, and the spleen and liver to determine spread (FIG. 2 b). The results showed that eIFN-α bp is not very important for replication at the initial site of infection because only minor differences in virus loads of the three viruses were found in the infected footpads at every time PI. However, the virus loads of Δ166 were ˜10⁴ and ˜10³ fold lower in spleen and liver, respectively, than those of WT or Rev166 indicating that eIFN-α bp is required for the efficient spread of ECTV to visceral organs.

In mousepox susceptible Balb/c mice, the massive replication of ECTV in the liver results in acute liver necrosis and death within 8-11 days PI. Any Balb/c mouse that survives this phase develops a typical skin exanthema and experiences weight loss of 25-30% of the initial body weight (14-17). Thus, to determine the role of eIFN-α bp in ECTV virulence we infected Balb/c mice with 300 PFU of ECTV Δ166, Rev 166 or WT. Strikingly, all of the mice infected with Δ166 survived while all of those infected with Rev166 or WT succumbed (FIG. 2 c). Moreover, none of the mice infected with Δ166 demonstrated overt symptoms of mousepox or major weight loss (not shown). Consistent with these results, infection with Δ166 resulted in decreased anatomical pathology in organs. Macroscopic observation showed that, as expected, the D-LNs and spleen of mice infected with WT ECTV were reduced in size compared to naïve mice and their spleens and livers were necrotic. Conversely, the D-LNs and spleens of mice infected with Δ166 were enlarged and their livers had a normal appearance (FIG. 3). In additional experiments we found that the dose of ECTV WT or Rev166 that killed 50% (LD50) of Balb/c mice was 0.1 PFU while as little as 1 PFU resulted in the death of 100% of the mice (not shown). In contrast, no deaths were observed in Balb/c mice (n=5) infected with 10⁷ PFU Δ166, the maximum dose that our virus stock permitted. Thus, from these experiments we conclude that Δ166 is attenuated at least 10⁸ fold considering 0.1 PFU the LD50 for WT and Rev166, and >10⁷ for Δ166. Because Rev166 was as virulent as WT, we also conclude that the only defect of Δ166 is in the production of eIFN-α bp. Together, this set of data demonstrates that eIFN-α bp is essential for ECTV virulence.

eIFN-α bp Decreases Innate and Adaptive Immunity

We and others have shown that T cells are essential for the natural resistance of B6 mice to mousepox (18-21) and that a very strong T cell response can be detected in the D-LN of B6 mice 5 days PI (22). We have also recently shown that, in contrast to B6 mice, the T cell response to WT ECTV in the D-LN of mousepox-susceptible naïve Balb/c mice is almost undetectable (17). Interestingly, naïve Balb/c mice mounted a very strong CD8⁺ T cell response to Δ166 but, as we showed previously, not to Rev166 (FIG. 4 a). A similar observation was made for the CD4⁺ T cell response (not shown). In addition, we also found an increase in the T cell response to Δ166 as compared to Rev166 in mousepox resistant B6 mice (not shown). Thus, one major effect of eIFN-α bp is to decrease the T cell response.

We next tested whether eIFN-α bp may also affect innate immunity. When RAG-1 KO mice (that lack adaptive immunity) were infected with Δ166, they succumbed to mousepox but several days later than those infected with Rev166 (FIG. 4 b) indicating that in addition to adaptive immunity, eIFN-α bp affects innate immunity. We reasoned that NK cells might be one component of innate immunity affected by eIFN-α bp because NK cells are essential for resistance to mousepox (24, 25). In addition, recent experiments from the Buller laboratory (25) as well as our own experiments showed that on day 2 PI, ECTV recruits NK cells to the D-LN. ECTV Δ166 recruited in excess of four times more NK cells to the D-LN than Rev166 (FIG. 4 c) or WT (not shown) indicating that one effect of eIFN-α bp on innate immunity is to reduce the recruitment of NK cells to the D-LN. However, eIFN-α bp must also affect components of innate immunity other than NK cells (e.g. macrophages and/or polymorphonuclear cells) because RAG-1 KO mice depleted of NK cells with anti-Asialo GM1 Ab and infected with ECTV Δ166, succumbed to mousepox later than those infected with Rev166 (FIG. 4 d).

eIFN-α bp is a Natural Target of the Anti-OPV Ab Response

Infection with OPVs induces strong Ab response against multiple structural components of the virions (21, 24-26). Consistent with this, anti-sera to ECTV WT, Δ166 or Rev166 contained Abs that recognized virions in cell lysates (FIG. 5 a). However, whether secreted IRMs can also be targets of the Ab response is not known. This question is important because Abs capable of blocking the function of IRMs essential for virus virulence could contribute to protective immunity. To elucidate whether eIFN-α bp is a natural target of the Ab response, we cloned and produced in E. coli recombinant His-tagged eIFN-α bp (Rec eIFN-α bp) which was recovered from inclusion bodies and purified by Ni²⁺-affinity chromatography (not shown). After refolding, Rec eIFN-α bp bound IFN-α (FIG. 5 b), inactivated IFN-α but not −β in tissue culture (FIG. 5 c) and, more interestingly, complemented Δ166 in vivo: i.e. when Balb/c mice infected with Δ166 were also inoculated with Rec eIFN-α bp, they succumbed to mousepox (FIG. 5 d) but not when inoculated with rec IFN-α bp alone. We next used Rec eIFN-α bp as antigen in ELISA to demonstrate that C57BL/6 mice that recovered from infection with Rev166 had high titer Abs to eIFN-α bp (FIG. 5 e, squares) indicating that, indeed, eIFN-α bp is a natural target of anti-ECTV immunity. Sera from Balb/c mice that had been infected with vaccinia virus (VACV, the OPV used as the smallpox vaccine) also reacted with Rec eIFN-α bp (FIG. 5 e, circles) indicating that VACV infection induces Abs to the eIFN-α bp homolog (B18R) and that Abs to the two proteins are cross-reactive. As expected, mice that had been infected with Δ166 did not have Abs to eIFN-α bp (FIG. 5 e, triangles). Even more important, sera from mice that recovered from Rev166 but not from Δ166 infection had the capacity to block the biological activity of Rec eIFN-α bp in tissue culture (FIG. 5 f) suggesting that Abs to eIFN-α bp may have protective effects in vivo.

Immunization with Recombinant eIFN-α bp Prevents Lethal Mousepox

Given that eIFN-α bp is essential for ECTV virulence in Balb/c mice and that Abs can neutralize its effects in vitro, we next tested whether immunization with Rec eIFN-α by induced a protective immune response. As expected, sera from Rec eIFN-α bp immunized Balb/c mice had high Ab titers to eIFN-α bp (FIG. 6 a) and also neutralized the biological activity of Rec eIFN-α bp but not ECTV infectivity in tissue culture (not shown). Strikingly, all Balb/c mice immunized with Rec eIFN-α bp and challenged with 300 PFU ECTV WT (i.e. 3×10³ LD50) survived the infection with minimal weight loss (˜10%), while all mice immunized with control Rec human Her2/neu perished (FIG. 6 b). Thus, anti-eIFN-α bp antibodies protect from mousepox and Rec eIFN-α bp can be successfully used as a vaccine to prevent it.

Immunization with Sera Obtained from Rabbits Exposed to Recombinant eIFN-α by Prevents Lethal Mousepox

To test whether passive immunization with Abs to eIFN-α bp can protect from mousepox before and/or after exposure to ECTV, we immunized rabbits with Rec eIFN-α bp. ELISA experiments showed that their sera contained high titer Ab to the protein (not shown). To determine whether these rabbit Abs to eIFN-α bp can protect mice from mousepox either pre- or post-exposure, mice infected with ECTV (3000 PFU) were given 100 μl of the rabbit antisera twice on days 0 (before infection) and 3, or once on days 0, 3 or 5 PI. Mice receiving pre-immune sera served as a control. The data in FIG. 7 show that strong protection was achieved even for mice that received sera as late as day 5 PI. This data demonstrates that Abs to virulence factors can protect from OPV pre- and post-exposure.

We have also produced monoclonal Abs (mAbs) specific for the eIFN-α bp and tested one of them for protection. We found that one single dose of 1 mg mAb on day 2 PI protected 60% of the mice from mousepox and death and delayed death in the remaining 40% by 5-10 days (not shown). Thus, protection from viral infection can be obtained using a mAb directed against a target SPVP.

Passive Immunization with Anti-T1-IFNbp Antibodies Protects Against Mousepox by Blocking the Biological Function of T1-IFNbp

To study the basis of the protective effect of anti-T1-IFNbp antibodies, we made mouse monoclonal antibodies (mAbs) against the T1-IFNbp and used a bioassay to identify a blocking (MB-mAb) and a non-blocking (MNB-mAb) (FIG. 8A). Both mAbs bound to the T1-IFNbp-ECTV as evidenced by staining cultures of infected cells (FIG. 8B). Importantly, MB-mAb (FIG. 8C) and MNB-mAb (not shown) recognized not only T1-IFNbp-ECTV but also T1-IFNbp-VARV, -MPXV and -VACV bound to the surface of cells. Moreover, MB-mAb blocked the biological activity of T1-IFNbp VARV (FIG. 8D) as well as T1-IFNbp-MPXV (not shown). The isotype of both mAbs was IgG1 (not shown), which is a poor activator of the complement cascade and ADCC.

MB-mAb and MNB-mAb were compared for ability to protect against lethal mousepox using BALB/c mice infected with ECTV-Luc. Five days post infection (dpi) the mice were treated with MB-mAb and MNB-mAb, and their livers were collected 1 (day post treatment (dpt). We found that the mice treated with MB-mAb had a significant increase in the transcription of the ISGs Mx1 and IRF7 as compared with mice treated with MNB-mAb, even though there were no differences in the transcription of T1-IFN genes (only IFNα2 is shown, FIG. 9A), demonstrating that MB-mAb blocks the function of the T1-IFNbp in vivo and reestablishes T1-IFN signaling. Moreover, 1 dpt (6 dpi), the livers of mice treated with MB-mAb had marginal but significantly lower virus titers than the livers of mice treated with MNB-mAb, and this difference increased substantially 2 dpt, as detected by Luc activity in liver lysates (FIG. 9B). The differential effect on virus loads between MB-mAb and MNB-mAb 2 dpt can also be appreciated by in vivo whole animal imaging (FIG. 9C). Moreover, while the livers of mice treated with MNB-mAb were almost completely necrotic (indicated by the pink/bright areas lacking nuclei) and devoid of a mononuclear infiltrate, the livers of mice treated with MB-mAb showed only small areas of necrosis and had heavy infiltrates of mononuclear cells, in particular in the portal triad, which is indicative of an immune response (FIG. 9D). Finally, while mice treated with MNB-mAb succumbed to infection as readily as mice treated with control mouse IgG1, the mice treated with a single dose of MB-mAb 5 dpi were significantly protected from lethal mousepox while mice treated with MNB-mAb were not (FIG. 9E). Because MB-mAb protected while the MNB-mAb did not (even though both antibodies recognize T1-IFNbp at the surface of cells), these results demonstrate that protection is due to the blockade of the biological function of the T1-IFNbp and not to other immune mechanisms such as complement activation or antibody dependent cellular cytotoxicity (ADCC). These results are also consistent with the isotype of the mAbs, because IgG1 is not very effective in complement activation or ADCC. This is a desirable result because these two processes could induce immunopathology.

A MB-mAb to the T1-IFNbp-ECTV restores T-IFN signaling in the liver and is effective as a late therapy for an OPV disease. This MB-mAb is cross-reactive with T1-IFNbp-MPXV and T1-IFNbp-VARV. Together, these results provide supporting evidence that Abs that block T1-IFNbp-MPXV or T1-IFN-VARV can be effective as a therapy for MPXV VARY and other emerging OPV infections in humans or as a therapy for complications of smallpox vaccination.

Discussion

The data described here show that the eIFN-α bp of ECTV is absolutely essential for virulence. It is interesting to mention that a VACV lacking the EVM166 ortholog B18R was found to be only mildly attenuated in mice infected through the intranasal route (8). Of note, the exact reason for this attenuation was not clear because B18R has very low affinity for type I mouse IFNs (8). In addition, VACV is not a natural pathogen of the laboratory mouse and intranasal infection of mice with VACV does not reproduce the natural pathogenesis of OPV diseases. Thus, our demonstration that Δ166 is extremely attenuated further stresses the need to explore the role of virulence factors in animal species that have natural susceptibility to the virus in question. The finding that deletion of only one protein that is non-essential for virus replication results in a virus that is attenuated at least 10⁸-fold is very surprising and indicative of the important role of eIFN-α bp in ECTV virulence. In this regard, it has recently been shown that ECTV lacking the eIFN-γ by (EVM158) is only mildly attenuated because it spread substantially in vivo, and because it induced mousepox and some deaths in susceptible Balb/c mice even at doses of 500 PFU (28). Another important question is whether the type I IFN bp, which is conserved among most OPVs, is also essential for the virulence of other OPVs in their natural hosts or whether different IRMs will be essential for each virus-host interaction. This question will be more difficult to address as it requires matching viruses with natural hosts.

IFN-α and -β are known to use the same signaling pathway to induce the anti-viral state in cells (1). Because eIFN-α bp inactivates mouse IFN-α but not -β, and because no other IFN-β blocking activity was detected in supernatants of ECTV infected cells (7), the extreme attenuation of Δ166 is intriguing. Several possibilities could explain this conundrum, all of them enticing. One possibility is that besides IFN-α binding, the eIFN-α bp protein has a second function that is essential for virulence. This second function, however, would also have to be performed in the extracellular environment because inoculation of the recombinant protein rescued virulence of Δ166 and Abs to the eIFN-α bp induced by vaccination prevented mousepox following infection with WT ECTV. Another possibility is that IFN-β is not produced or produced in insufficient quantities during ECTV infection. Finally it is also possible that the in vivo anti-viral functions of IFN-α and -β are non-overlapping.

Because of the risks of emerging OPV infections and OPV weaponization, and because the VACV based vaccine is not safe by current standards, there is a considerable interest in developing novel anti-OPV vaccines (26, 28-35) . Our work also indicates that deletion of IRMs from live vaccines may be a double edged-sword. On one hand, it may increase the safety of the vaccine. However, it is also very possible that these deletions will decrease vaccine efficacy because, as we now know, the type I IFN by of OPVs are a natural target of the Ab response and are crossreactive. Thus, it is very possible that Abs to type I IFN bp and other IRMs may substantially contribute to the protective effects induced by live VACV vaccination and one of the reasons why immunization with killed virions is not very effective at inducing protection (37).

Vaccines against pathogen-secreted proteins are in use for bacterial diseases (e.g. tetanus, anthrax). However, the use of secreted virulence factors as vaccines to prevent viral diseases is unheard of. Thus, our work here provides the framework for a novel approach to anti-viral vaccination. It could be argued that such an approach may not be useful because it prevents disease but does not provide sterilizing immunity, thus maintaining the possibility of virus spread. This argument can be contested, however, because one of the biggest successes in medical history, VACV immunization, does not provide sterilizing immunity either to humans or mice (16, 17). In the case of subunit vaccines against OPVs, all approaches thus far have focused on structural proteins with some success (26, 28-30, 32). Given the strong protection induced by Rec eIFN-α bp we now propose that combining essential IRMs and structural proteins in new vaccine formulations may be the best approach for an effective and safe subunit vaccine to OPVs and possibly other viruses. In addition, our experiments open the possibility that the type I IFN bp of OPVs could be used as a pharmacological target to prevent disease in individuals exposed or at risk of exposure to pathogenic OPVs.

We also describe antibody based reagents which can be optimized and optionally humanized, such as the blocking mAb (HB-mAb) to the OPV T1-IFNbp described above. These reagents will be tested in preclinical mouse and non-human primate (NHP) models as a late therapy for OPV infections in humans. Our data suggest that a HB-mAb that promiscuously blocks the activity of T1IFNbp from various OPVs will be an effective late therapy for VARV, MPXV and other emerging OPV infections in humans, and also in cases of smallpox vaccine complications. The demonstration that a MB-mAb to the T1IFNbp-ECTV can be used as an effective treatment against mousepox at relatively late stages of ECTV infection and our finding that the MB-mAb is promiscuous because it not only binds and blocks T1-IFNbp-ECTV but also T1-IFNbp-VARV, T1-IFNbp-MPXV and T1-IFNbp-VACV is particularly intriguing. These data provide the means to exploit these reagents in new and efficacious methods for the treatment of pox infection.

References and Notes

-   1. Sen, G. C. 2001. Viruses and interferons. Annual review of     microbiology 55:255-281. -   2. Stetson, D. B., and R. Medzhitov. 2006. Type I interferons in     host defense. Immunity 25:373-381. -   3. Vilcek, J. 2006. Fifty years of interferon research: aiming at a     moving target. Immunity 25:343-348. -   4. Grandvaux, N., B. R. tenOever, M. J. Servant, and J.     Hiscott. 2002. The interferon antiviral response: from viral     invasion to evasion. Current opinion in infectious diseases     15:259-267. -   5. Seet, B. T., J. B. Johnston, C. R. Brunetti, J. W. Barrett, H.     Everett, C. Cameron, J. Sypula, S. H. Nazarian, A. Lucas, and G.     McFadden. 2003. Poxviruses and immune evasion. Annu Rev Immunol     21:377-423. -   6. Theofilopoulos, A. N., R. Baccala, B. Beutler, and D. H.     Kono. 2005. Type I interferons (alpha/beta) in immunity and     autoimmunity. Annu Rev Immunol 23:307-336. -   7. Smith, V. P., and A. Alcami. 2002. Inhibition of Interferons by     Ectromelia Virus. J. Virol. 76:1124-1134. -   8. Symons, J. A., A. Alcami, and G. L. Smith. 1995. Vaccinia virus     encodes a soluble type I interferon receptor of novel structure and     broad species specificity. Cell 81:551-560. -   9. Alcami, A., J. A. Symons, and G. L. Smith. 2000. The vaccinia     virus soluble alpha/beta interferon (IFN) receptor binds to the cell     surface and protects cells from the antiviral effects of IFN. J     Virol 74:11230-11239. -   10. Colamonici, O. R., P. Domanski, S. M. Sweitzer, A. Lamer,     and R. M. Buller. 1995. Vaccinia virus B18R gene encodes a type I     interferon-binding protein that blocks interferon alpha     transmembrane signaling. J Biol Chem 270:15974-15978. -   11. Chen, N., M. I. Danila, Z. Feng, R. M. Buller, C. Wang, X.     Han, E. J. Lefkowitz, and C. Upton. 2003. The genomic sequence of     ectromelia virus, the causative agent of mousepox. Virology     317:165-186. -   12. Fang, M., H. Cheng, Z. Dai, Z. Bu, and L. J. Sigal. 2006.     Immunization with a single extracellular enveloped virus protein     produced in bacteria provides partial protection from a lethal     orthopoxvirus infection in a natural host. Virology 345:231-243. -   13. Fang, M., and L. J. Sigal. 2005. Antibodies and CD8+ T Cells Are     Complementary and Essential for Natural Resistance to a Highly     Lethal Cytopathic Virus. J Immunol 175:6829-6836. -   14. Fang, M., and L. J. Sigal. 2006. Direct CD28 Costimulation is     Required for CD8+ T Cell-Mediated Resistance to an Acute Viral     Disease in a Natural Host. J Immunol 177:8027-8036. -   15. Xu, R.-H., M. Fang, A. Klein-Szanto, and L. J. Sigal. 2007.     Memory CD8+ T cells are gatekeepers of the lymph node draining the     site of viral infection. Proc Natl Acad Sci USA 104:10992-10997. -   16. Todaro, G. J., and H. Green. 1963. Quantitative studies of the     growth of mouse embryo cells in culture and their development into     established lines. J Cell Biol 17:299-313. -   17. Johnston, J. B., and G. McFadden. 2004. Technical knockout:     understanding poxvirus pathogenesis by selectively deleting viral     immunomodulatory genes. Cell Microbiol 6:695-705. -   18. Fenner, F. 1949. Mouse-pox; infectious ectromelia of mice; a     review. J Immunol 63:341-373. -   19. Esteban, D. J., and R. M. Buller. 2005. Ectromelia virus: the     causative agent of mousepox. J Gen Virol 86:2645-2659. -   20. Fenner, F. 1994. Mousepox (ectromelia). In Virus infections of     rodents and lagomorphs. A. Osterhaus, editor Elsevier Science,     Amsterdam; New York. 412. -   21. Fenner, F., D. A. Henderson, I. Arita, Z. Jezek, D. Ladnyi,     and W. H. Organization. 1988. Smallpox and its eradication. World     Health Organization, Geneva. 1460 pp. -   22. Blanden, R. V. 1971. Mechanisms of recovery from a generalized     viral infection: mousepox. II. Passive transfer of recovery     mechanisms with immune lymphoid cells. J Exp Med 133:1074-1089. -   23. Buller, R. M., K. L. Holmes, A. Hugin, T. N. Frederickson,     and H. C. Morse, 3rd. 1987. Induction of cytotoxic T-cell responses     in vivo in the absence of CD4 helper cells. Nature 328:77-79. -   24. Karupiah, G., R. M. Buller, N. Van Rooijen, C. J. Duarte, and J.     Chen. 1996. Different roles for CD4+ and CD8+ T lymphocytes and     macrophage subsets in the control of a generalized virus infection.     J Virol 70:8301-8309. -   25. Parker, A. K., S. Parker, W. M. Yokoyama, J. A. Corbett,     and R. M. Buller. 2007. Induction of natural killer cell responses     by ectromelia virus controls infection. J Virol 81:4070-4079. -   26. Davies, D. H., D. M. Molina, J. Wrammert, J. Miller, S.     Hirst, Y. Mu, J. Pablo, B. Unal, R. Nakajima-Sasaki, X. Liang, S.     Crotty, K. L. Karem, I. K. Damon, R. Ahmed, L. Villarreal, and P. L.     Feigner. 2007. Proteome-wide analysis of the serological response to     vaccinia and smallpox. Proteomics 7:1678-1686. -   27. Putz, M. M., C. M. Midgley, M. Law, and G. L. Smith. 2006.     Quantification of antibody responses against multiple antigens of     the two infectious forms of Vaccinia virus provides a benchmark for     smallpox vaccination. Nat Med 12:1310-1315. -   28. Sakala, I. G., G. Chaudhri, R. M. Buller, A. A. Nuara, H.     Bai, N. Chen, and G. Karupiah. 2007. Poxvirus-encoded gamma     interferon binding protein dampens the host immune response to     infection. Journal of virology 81:3346-3353. -   29. Hooper, J. W., D. M. Custer, C. S. Schmaljohn, and A. L.     Schmaljohn. 2000. DNA vaccination with vaccinia virus L1R and A33R     genes protects mice against a lethal poxvirus challenge. Virology     266:329-339. -   30. Hooper, J. W., D. M. Custer, and E. Thompson. 2003.     Four-gene-combination DNA vaccine protects mice against a lethal     vaccinia virus challenge and elicits appropriate antibody responses     in nonhuman primates. Virology 306:181-195. -   31. Hooper, J. W., E. Thompson, C. Wilhelmsen, M. Zimmerman, M. A.     Ichou, S. E. Steffen, C. S. Schmaljohn, A. L. Schmaljohn, and P. B.     Jahrling. 2004. Smallpox DNA Vaccine Protects Nonhuman Primates     against Lethal Monkeypox. J Virol 78:4433-4443. -   32. Snyder, J. T., I. M. Belyakov, A. Dzutsev, F. Lemonnier,     and J. A. Berzofsky. 2004. Protection against lethal vaccinia virus     challenge in HLA-A2 transgenic mice by immunization with a single     CD8+ T-cell peptide epitope of vaccinia and variola viruses. J Virol     78:7052-7060. -   33. Fogg, C., S. Lustig, J. C. Whitbeck, R. J. Eisenberg, G. H.     Cohen, and B. Moss. 2004. Protective immunity to vaccinia virus     induced by vaccination with multiple recombinant outer membrane     proteins of intracellular and extracellular virions. J Virol     78:10230-10237. -   34. Fulginiti, V. A., A. Papier, J. M. Lane, J. M. Neff, and D. A.     Henderson. 2003. Smallpox vaccination: a review, part II. Adverse     events. Clin Infect Dis 37:251-271. -   35. Edghill-Smith, Y., H. Golding, J. Manischewitz, L. R. King, D.     Scott, M. Bray, A. Nalca, J. W. Hooper, C. A. Whitehouse, J. E.     Schmitz, K. A. Reimann, and G. Franchini. 2005. Smallpox     vaccine-induced antibodies are necessary and sufficient for     protection against monkeypox virus. Nat Med -   36. Earl, P. L., J. L. Americo, L. S. Wyatt, L. A. Eller, J. C.     Whitbeck, G. H. Cohen, R. J. Eisenberg, C. J. Hartmann, D. L.     Jackson, D. A. Kulesh, M. J. Martinez, D. M. Miller, E. M.     Mucker, J. D. Shamblin, S. H. Zwiers, J. W. Huggins, P. B. Jahrling,     and B. Moss. 2004. Immunogenicity of a highly attenuated MVA     smallpox vaccine and protection against monkeypox. Nature     428:182-185. -   37. Galmiche, M. C., J. Goenaga, R. Wittek, and L.     Rindisbacher. 1999. Neutralizing and protective antibodies directed     against vaccinia virus envelope antigens. Virology 254:71-80.

EXAMPLE II

While infection with mouse pox is exemplified in Example I, the compositions and methods described therein may be adapted for the treatment and prevention of other pox virus infections.

For example, humans could be immunized against small pox using a similar approach. The PBR Gene Record for the Variola virus strain Bangladesh 1974 (nur islam) is listed under VARV-BGD74_nur:glycoprotein. The targeted protein binds type-I interferons; similar to VACV-WR-200 and VACV-COP-B19R; which are immunoglobulin superfamily secreted proteins and host defense modulators. The amino acid sequence for the SPVP of this strain of small pox is provided at GenBank accession number: ABF23761. The availability of the sequence information for this protein facilitates the recombinant production and purification of large quantities thereof. SPVP antigens may be produced using any number of recombinant expression systems. The protein may be produced in E. coli, yeast, insect or mammalian cells using suitable expression vectors well known to the skilled artisan. Once the protein is purified, it may be used to immunize patients via subcutaneous injection of sufficient quantities in a biological carrier to generate a protective immune response via active immunization. Booster injections may also be administered as needed.

Alternatively, humanized monoclonal antibodies to the smallpox SPVP could be generated either via immunization of the XENOMOUSE® with the small pox SPVP or genetic engineering of the antigen binding regions on to a humanized antibody framework after production in a suitable host animal. Once the humanized antibodies are produced, suitable quantities may be passively administered to a human patient to treat and/or prevent small pox infection. Thus, humanized monoclonal antibodies to the SPVP listed herein or functional fragments thereof are also encompassed by the present invention.

Other preferred SPVP proteins from small pox and their GenBank accession numbers are listed below. The skilled person can readily adapt the protocols described above to generate a protective immune response to the SPVP listed.

-   PBR Gene Record for: VARV-BGD74_nur:CC-chemokine-binding protein -   Virus: Variola virus strain Bangladesh 1974 (nur islam) -   Protein function: similar to VACV-WR-218; VACV-COP-C23L:B29R; host     defense modulator -   GenBank accession number: ABF23769 -   PBR Gene Record for: VARV-BGD74_nur:Crm-B secreted     TNF-alpha-receptor-like protein -   Virus: Variola virus strain Bangladesh 1974 (nur islam) -   Protein function: similar to VACV-WR-215; host defense modulator -   GenBank accession number: ABF23768 -   PBR Gene Record for: VARV-BGD74_nur:IL-1-beta-inhibitor -   Virus: Variola virus strain Bangladesh 1974 (nur islam) -   Protein function: similar to part of VACV-WR-197; part of     VACV-COP-B16R; host defense modulator -   GenBank accession number: ABF23758 -   PBR Gene Record for: VARV-BGD74_nur:interferon-gamma receptor-like     soluble protein -   Virus: Variola virus strain Bangladesh 1974 (nur islam) -   Protein function: similar to VACV-WR-190; VACV-COP-B8R; host defense     modulator -   GenBank accession number: ABF23752

It may also be desirable to actively or passively immunize a human patient against monkeypox. Suitable SPVP from monkeypox and their GenBank Accession numbers are provided below. As with the SPVP from smallpox, the SPVP from monkey pox can be employed in the methods described above to generate a robust immune response against this particular virus.

-   PBR Gene Record for: MPXV-USA_(—)2003_(—)039:192 -   Virus: Monkeypox virus strain USA_(—)2003_(—)039 -   Protein function: IFN-alpha-beta-receptor-like secreted glycoprotein -   GenBank accession number: AAY97783 -   PBR Gene Record for: MPXV-USA_(—)2003_(—)039:001 -   Virus: Monkeypox virus strain USA_(—)2003_(—)039 -   Protein function: chemokine-binding protein -   GenBank accession number: AAY97599 -   PBR Gene Record for: MPXV-USA_(—)2003_(—)039:002 -   Virus: Monkeypox virus strain USA_(—)2003_(—)039 -   Protein function: TNF-alpha-receptor-like protein -   GenBank accession number: AAY97600 -   PBR Gene Record for: MPXV-USA_(—)2003_(—)039:189 -   Virus: Monkeypox virus strain USA_(—)2003_(—)039 -   Protein function: bifunctional IL-1-beta-inhibitor-prevents febrile     response in VAC-mouse intranasal model -   GenBank accession number: AAY97780 -   PBR Gene Record for: MPXV-USA_(—)2003_(—)039:183 -   Virus: Monkeypox virus strain USA_(—)2003_(—)039 -   Protein function: soluble interferon-gamma receptor-like protein -   GenBank accession number: AAY97774

As discussed at length hereinabove, there are many different pox viruses which cause disease in both human and animal populations. Tables I-XI provide additional SPVP targets and the virus species and gene name for developing anti-pox vaccines against the cognate virus. Each of the SPVP listed can be utilized to stimulate an immune response and thereby treat or prevent invention with the cognate virus.

TABLE I Viral Orthologous Clusters V2.0 (VOCs) C-type lectins Gene Results Table Genome name Genus Genome id Ortholog Group Name Ortholog Group ID Gene number Gene id Genbank id Genbank name Bovine papular stomatitis virus strain Parapoxvirus 1505 C-type lectin-like EEV protein 374 BPSV-AR02-110 43450 41018862 109 BV-AR02 (Cop-A34R) Camelpox virus strain CMS Orthopoxvirus 1493 C-type lectin-like EEV protein 374 CMLV-CMS-194 41290 19718122 151R (Cop-A34R) Camelpox virus strain M96 Orthopoxvirus 1491 C-type lectin-like EEV protein 374 CMLV-M96-155 40861 18640387 153 (Cop-A34R) Canarypox virus strain ATCC VR111 Avipoxvirus 1506 C-type lectin-like EEV protein 374 CNPV-VR111-272 43745 40556210 272 (Cop-A34R) Cowpox virus strain Brighton Red Orthopoxvirus 1496 C-type lectin-like EEV protein 374 CPXV-BR-175 41874 20178532 169 (Cop-A34R) Cowpox virus strain GRI-90 Orthopoxvirus 1501 C-type lectin-like EEV protein 374 CPXV-GRI-159 42816 30519527 A35R (Cop-A34R) Cowpox virus strain Germany 91-3 Orthopoxvirus 2214 C-type lectin-like EEV protein 374 CPXV-GER91-158 56533 90660391 IEV and EEV (Cop-A34R) outer membrane lectin-like glycoprotein Deerpox virus strain W-1170-84 Unclassified 1516 C-type lectin-like EEV protein 374 DPV-W1170_84-131 45414 0 133 (Cop-A34R) Deerpox virus strain W-848-83 Unclassified 1515 C-type lectin-like EEV protein 374 DPV-W848_83-131 45244 62637510 133 (Cop-A34R) Ectromelia virus strain Moscow Orthopoxvirus 1492 C-type lectin-like EEV protein 374 ECTV-Mos-140 41059 22164742 136 (Cop-A34R) Ectromelia virus strain Naval Orthopoxvirus 1499 C-type lectin-like EEV protein 374 ECTV-Nav-143 42398 0 156 (Cop-A34R) Fowlpox virus strain HP1-438 Munich Avipoxvirus 1509 C-type lectin-like EEV protein 374 FWPV-HP1_438-190 44263 41023482 fp9.198 (Cop-A34R) Fowlpox virus strain Iowa Avipoxvirus 1476 C-type lectin-like EEV protein 374 FWPV-Iowa-200 37932 9634868 198 (Cop-A34R) Goatpox virus strain G20-LKV Capripoxvirus 1514 C-type lectin-like EEV protein 374 GTPV-G20LKV-122 45082 0 118 (Cop-A34R) Goatpox virus strain Pellor Capripoxvirus 1513 C-type lectin-like EEV protein 374 GTPV-Pellor-121 44931 0 118 (Cop-A34R) Horsepox virus strain MNR-76 Orthopoxvirus 2230 C-type lectin-like EEV protein 374 HSPV-MNR76-177 59814 111184344 HSPV155 (Cop-A34R) Lumpy skin disease virus strain Capripoxvirus 1488 C-type lectin-like EEV protein 374 LSDV-Nee-125 40328 15150562 123 Neethling 2490 (Cop-A34R) Lumpy skin disease virus strain Capripoxvirus 1497 C-type lectin-like EEV protein 374 LSDV-NW_LW-127 42061 22595658 123 Neethling Warmbaths LW (Cop-A34R) Lumpy skin disease virus strain Capripoxvirus 1498 C-type lectin-like EEV protein 374 LSDV-LW1959-126 42220 22595816 123 Neethling vaccine LW 1959 (Cop-A34R) Molluscum contagiosum virus strain Molluscipoxvirus 1477 C-type lectin-like EEV protein 374 MOCV-st1-144 38138 9629075 143R subtype 1 (Cop-A34R) Monkeypox Virus strain Walter Reed Orthopoxvirus 1502 C-type lectin-like EEV protein 374 MPXV-WR267-141 43012 0 140 267 (Cop-A34R) Monkeypox virus strain COP-58 Orthopoxvirus 1520 C-type lectin-like EEV protein 374 MPXV-COP58-140 46445 59858946 140 (Cop-A34R) Monkeypox virus strain Orthopoxvirus 1524 C-type lectin-like EEV protein 374 MPXV-COG_2003_358- 47209 68449026 154 Congo_2003_358 (Cop-A34R) Monkeypox virus strain Orthopoxvirus 1525 C-type lectin-like EEV protein 374 MPXV-LBR_1970_184-1 47406 68449427 154 Liberia_1970_184 (Cop-A34R) Monkeypox virus strain Sierra Leone Orthopoxvirus 1521 C-type lectin-like EEV protein 374 MPXV-SLE-140 46622 58220610 140 (Cop-A34R) Monkeypox virus strain Orthopoxvirus 1526 C-type lectin-like EEV protein 374 MPXV-USA_2003_039- 47605 68449627 154 USA_2003_039 (Cop-A34R) Monkeypox virus strain Orthopoxvirus 1522 C-type lectin-like EEV protein 374 MPXV-USA_2003_044- 46807 68448825 154 USA_2003_044 (Cop-A34R) Monkeypox virus strain Zaire Orthopoxvirus 1489 C-type lectin-like EEV protein 374 MPXV-ZAR-149 40510 17975059 A36R (Cop-A34R) Monkeypox virus strain Zaire_1979- Orthopoxvirus 1523 C-type lectin-like EEV protein 374 MPXV-ZAR_1979_005- 47008 68449228 154 005 (Cop-A34R) Myxoma virus strain Lausanne Leporipoxvirus 1479 C-type lectin-like EEV protein 374 MYXV-Lau-127 38551 9633758 m122R (Cop-A34R) Orf virus strain NZ2 Parapoxvirus 1527 C-type lectin-like EEV protein 374 ORFV-NZ2-109 47764 74230823 110 (Cop-A34R) Orf virus strain NZ2 Patent Parapoxvirus 1504 C-type lectin-like EEV protein 374 ORFV-NZ2_Pat-115 43304 32167504 112 WO03006654 (Cop-A34R) Orf virus strain OV-IA82 Parapoxvirus 1507 C-type lectin-like EEV protein 374 ORFV-IA82-110 43911 41018597 107 (Cop-A34R) Orf virus strain OV-SA00 Parapoxvirus 1508 C-type lectin-like EEV protein 374 ORFV-SA00-110 44047 41018730 107 (Cop-A34R) Rabbit fibroma virus strain Kasza Leporipoxvirus 1480 C-type lectin-like EEV protein 374 SFV-Kas-127 38722 9633932 gp122R (Cop-A34R) Rabbitpox virus strain Utrecht Orthopoxvirus 1494 C-type lectin-like EEV protein 374 RPXV-Utr-144 41506 44971505 142 (Cop-A34R) Sheeppox virus strain A Capripoxvirus 1511 C-type lectin-like EEV protein 374 SPPV-A-121 44630 0 118 (Cop-A34R) Sheeppox virus strain NISKHI Capripoxvirus 1512 C-type lectin-like EEV protein 374 SPPV-NISKHI-120 44779 0 118 (Cop-A34R) Sheeppox virus strain TU-V02127 Capripoxvirus 1495 C-type lectin-like EEV protein 374 SPPV-TU-121 41669 21492575 118 (Cop-A34R) Swinepox virus strain Nebraska 17077- Suipoxvirus 1490 C-type lectin-like EEV protein 374 SWPV-Neb-121 40676 18640206 120 99 (Cop-A34R) Tanapox virus strain Kenya Yatapoxvirus 3496 C-type lectin-like EEV protein 374 TANV-KEN-128 67634 146746463 123R (Cop-A34R) Tanapox virus strain isolate TPV-RoC Yatapoxvirus 3497 C-type lectin-like EEV protein 374 TANV-COD-127 67739 146746619 123R (Cop-A34R) Taterapox virus strain Dahomey 1968 Orthopoxvirus 2195 C-type lectin-like EEV protein 374 TATV-DAH68-158 53076 113195335 IEV and EEV (Cop-A34R) outer membrane lectin-like glycoprotein Vaccinia virus strain 3737 Orthopoxvirus 1528 C-type lectin-like EEV protein 374 VACV-3737-159 47947 88900775 153 (Cop-A34R) Vaccinia virus strain Acambis 2000 Orthopoxvirus 2161 C-type lectin-like EEV protein 374 VACV-Acam2000-166 51222 38349024 168 (Cop-A34R) Vaccinia virus strain Acambis 3 Orthopoxvirus 2162 C-type lectin-like EEV protein 374 VACV-Acam3-168 51459 37551602 168 (Cop-A34R) Vaccinia virus strain Acambis 3000 Orthopoxvirus 1510 C-type lectin-like EEV protein 374 VACV-Acam3000-149 44463 47088473 147 Modified Virus Ankara (Cop-A34R) Vaccinia virus strain Copenhagen Orthopoxvirus 1485 C-type lectin-like EEV protein 374 VACV-Cop-197 39722 335509 A34R (Cop-A34R) Vaccinia virus strain DUKE Orthopoxvirus 2458 C-type lectin-like EEV protein 374 VACV-DUKE-165 63545 90819817 165 (Cop-A34R) Vaccinia virus strain LC16m8 Orthopoxvirus 1517 C-type lectin-like EEV protein 374 VACV-LC16m8-211 45664 56713550 m8201R (Cop-A34R) Vaccinia virus strain LC16mO Orthopoxvirus 1518 C-type lectin-like EEV protein 374 VACV-LC16mO-211 45948 56713834 mO201R (Cop-A34R) Vaccinia virus strain Lister Orthopoxvirus 1519 C-type lectin-like EEV protein 374 VACV-Lister-211 46232 0 m8201R (Cop-A34R) Vaccinia virus strain Lister_VACV107 Orthopoxvirus 2659 C-type lectin-like EEV protein 374 VACV-Lister_VACV107- 64487 88854227 List150 (Cop-A34R) Vaccinia virus strain MVA-I721 Orthopoxvirus 2696 C-type lectin-like EEV protein 374 VACV-MVA_I721-132 65345 0 147 (Cop-A34R) Vaccinia virus strain Western Reserve Orthopoxvirus 1500 C-type lectin-like EEV protein 374 VACV-WR-157 42596 66275954 157 (Cop-A34R) Vaccinia virus strain modified vaccinia Orthopoxvirus 1484 C-type lectin-like EEV protein 374 VACV-MVA-129 65541 2772790 MVA145R Ankara (Cop-A34R) Variola major virus strain Bangladesh Orthopoxvirus 1481 C-type lectin-like EEV protein 374 VARV-BGD75maj-147 38908 439058 A37R 1975 (Cop-A34R) Variola minor virus strain Garcia 1966 Orthopoxvirus 1482 C-type lectin-like EEV protein 374 VARV-Gar_1966-150 39103 5830702 A38R (Cop-A34R) Variola virus strain Afghanistan 1970 Orthopoxvirus 2197 C-type lectin-like EEV protein 374 VARV-AFG70-146 53490 109724185 glycoprotein Variolator 4 (Cop-A34R) Variola virus strain Bangladesh 1974 Orthopoxvirus 2216 C-type lectin-like EEV protein 374 VARV-BGD74_shz-146 56938 94484803 glycoprotein (Shahzaman) (Cop-A34R) Variola virus strain Bangladesh 1974 Orthopoxvirus 2217 C-type lectin-like EEV protein 374 VARV-BGD74_sol-146 57136 94485001 glycoprotein (Solaiman) (Cop-A34R) Variola virus strain Bangladesh 1974 Orthopoxvirus 2215 C-type lectin-like EEV protein 374 VARV-BGD74_nur-146 56740 94484605 glycoprotein (nur islam) (Cop-A34R) Variola virus strain Bangladesh 1975 Orthopoxvirus 2198 C-type lectin-like EEV protein 374 VARV-BGD75_Banu-14 53693 109724389 glycoprotein v75-550 Banu (Cop-A34R) Variola virus strain Benin, Dahomey Orthopoxvirus 2224 C-type lectin-like EEV protein 374 VARV-BEN68-148 58558 94483788 glycoprotein 1968 (v68-59) (Cop-A34R) Variola virus strain Botswana 1972 Orthopoxvirus 2225 C-type lectin-like EEV protein 374 VARV-BWA72-146 58765 94483993 glycoprotein (v72-143) (Cop-A34R) Variola virus strain Botswana 1973 Orthopoxvirus 2226 C-type lectin-like EEV protein 374 VARV-BWA73-146 58967 94484196 glycoprotein (v73-225) (Cop-A34R) Variola virus strain Brazil 1966 (v66-39 Orthopoxvirus 2227 C-type lectin-like EEV protein 374 VARV-BRA66-150 59173 94484401 glycoprotein Sao Paulo) (Cop-A34R) Variola virus strain China Horn 1948 Orthopoxvirus 2203 C-type lectin-like EEV protein 374 VARV-CHN48-146 54306 109724591 glycoprotein Sabin Lab July 1948 (Cop-A34R) Variola virus strain Congo 1970 v70-46 Orthopoxvirus 2229 C-type lectin-like EEV protein 374 VARV-COG70_46-146 59581 109724796 glycoprotein Kinshasa (Cop-A34R) Variola virus strain Congo 9 1970 (v74- Orthopoxvirus 2228 C-type lectin-like EEV protein 374 VARV-COG70_227-146 59380 94485199 glycoprotein 227 Gispen) (Cop-A34R) Variola virus strain Ethiopia 1972 Orthopoxvirus 2231 C-type lectin-like EEV protein 374 VARV-ETH72_16-147 60020 94485401 glycoprotein (Eth16 R14-1X-72 Addis) (Cop-A34R) Variola virus strain Ethiopia 1972 Orthopoxvirus 2232 C-type lectin-like EEV protein 374 VARV-ETH72_17-147 60223 94485604 glycoprotein (Eth17 R14-1X-72 Addis) (Cop-A34R) Variola virus strain Germany 1958 Orthopoxvirus 2233 C-type lectin-like EEV protein 374 VARV-DEU58-145 60422 109724999 glycoprotein Heidelberg (Cop-A34R) Variola virus strain Guinea 1969 (005) Orthopoxvirus 2234 C-type lectin-like EEV protein 374 VARV-GIN69-148 60626 94485806 glycoprotein (Cop-A34R) Variola virus strain India 1953 (Kali- Orthopoxvirus 2238 C-type lectin-like EEV protein 374 VARV-IND53_mad-146 61436 94486009 glycoprotein Muthu-M50 Madras) (Cop-A34R) Variola virus strain India 1953 (New Orthopoxvirus 2239 C-type lectin-like EEV protein 374 VARV-IND53_ndel-145 61636 94486210 glycoprotein Delhi) (Cop-A34R) Variola virus strain India 1964 7124 Orthopoxvirus 2240 C-type lectin-like EEV protein 374 VARV-IND64_vel4-147 61840 109725203 glycoprotein Vellore (Cop-A34R) Variola virus strain India 1964 7125 Orthopoxvirus 2241 C-type lectin-like EEV protein 374 VARV-IND64_vel5-146 62044 109725408 IEV and EEV Vellore (Cop-A34R) outer membrane lectin-like glycoprotein Variola virus strain India 3 Major 1967 Orthopoxvirus 1483 C-type lectin-like EEV protein 374 VARV-IND3_1967-144 39306 9627662 A37R (Cop-A34R) Variola virus strain Iran 1972 2602 Orthopoxvirus 2235 C-type lectin-like EEV protein 374 VARV-IRN72-146 60831 109725611 glycoprotein Tabriz (Cop-A34R) Variola virus strain Japan 1946 Orthopoxvirus 2243 C-type lectin-like EEV protein 374 VARV-JPN46_yam-145 62420 94486413 glycoprotein (Yamada MS-2(A) Tokyo) (Cop-A34R) Variola virus strain Japan 1951 Orthopoxvirus 2244 C-type lectin-like EEV protein 374 VARV-JPN51_hrpr-145 62622 94486616 glycoprotein (Harper, Masterseed) (Cop-A34R) Variola virus strain Japan 1951 Orthopoxvirus 2245 C-type lectin-like EEV protein 374 VARV-JPN51_stwl-145 62823 94486818 glycoprotein (Stillwell, Masterseed) (Cop-A34R) Variola virus strain Korea 1947 (Lee, Orthopoxvirus 2236 C-type lectin-like EEV protein 374 VARV-KOR47-146 61034 94487021 glycoprotein Masterseed) (Cop-A34R) Variola virus strain Kuwait 1967 Orthopoxvirus 2237 C-type lectin-like EEV protein 374 VARV-KWT67-146 61236 94487224 glycoprotein (K1629) (Cop-A34R) Variola virus strain Nepal 1973 V73- Orthopoxvirus 2221 C-type lectin-like EEV protein 374 VARV-NPL73-146 57936 109725815 glycoprotein 175 (Cop-A34R) Variola virus strain Niger 1969 (001, Orthopoxvirus 2222 C-type lectin-like EEV protein 374 VARV-NER69-149 58142 94487426 glycoprotein importation from Nigeria) (Cop-A34R) Variola virus strain Sierra Leone 1969 Orthopoxvirus 2223 C-type lectin-like EEV protein 374 VARV-SLE68-149 58351 94488035 glycoprotein (V68-258) (Cop-A34R) Variola virus strain Somalia 1977 (V77- Orthopoxvirus 2218 C-type lectin-like EEV protein 374 VARV-SOM77_1252-14 57334 94488238 glycoprotein 1252) (Cop-A34R) Variola virus strain Somalia 1977 (V77- Orthopoxvirus 2219 C-type lectin-like EEV protein 374 VARV-SOM77_1605-14 57534 94488438 glycoprotein 1605) (Cop-A34R) Variola virus strain Somalia 1977 V77- Orthopoxvirus 2220 C-type lectin-like EEV protein 374 VARV-SOM77_ali-146 57734 109726222 glycoprotein 2479 (Cop-A34R) Variola virus strain South Africa 1965 Orthopoxvirus 2210 C-type lectin-like EEV protein 374 VARV-ZAF65_102-146 55718 94487630 glycoprotein (102 Natal, Ingwavuma) (Cop-A34R) Variola virus strain South Africa 1965 Orthopoxvirus 2211 C-type lectin-like EEV protein 374 VARV-ZAF65_103-146 55919 94487831 glycoprotein (103 Tvaal, Nelspruit) (Cop-A34R) Variola virus strain Sudan 1947 (Juba) Orthopoxvirus 2212 C-type lectin-like EEV protein 374 VARV-SDN47_jub-146 56120 94488638 IEV and EEV (Cop-A34R) outer membrane lectin-like glycoprotein Variola virus strain Sudan 1947 Orthopoxvirus 2213 C-type lectin-like EEV protein 374 VARV-SDN47_rum-146 56320 94488839 glycoprotein (Rumbec) (Cop-A34R) Variola virus strain Sumatra 1970 V70- Orthopoxvirus 2208 C-type lectin-like EEV protein 374 VARV-SUM70_222-145 55315 109726424 glycoprotein 222 (Cop-A34R) Variola virus strain Sumatra 1970 V70- Orthopoxvirus 2209 C-type lectin-like EEV protein 374 VARV-SUM70_228-145 55517 94489039 glycoprotein 228 (Cop-A34R) Variola virus strain Syria 1972 V72-199 Orthopoxvirus 2206 C-type lectin-like EEV protein 374 VARV-SYR72-146 54912 109726628 glycoprotein (Cop-A34R) Variola virus strain Tanzania 1965 Orthopoxvirus 2207 C-type lectin-like EEV protein 374 VARV-TZA65-146 55115 94489239 glycoprotein kembula (Cop-A34R) Variola virus strain United Kingdom Orthopoxvirus 2204 C-type lectin-like EEV protein 374 VARV-GBR44_harv-146 54511 94489439 glycoprotein 1946 Harvey (Cop-A34R) Variola virus strain United Kingdom Orthopoxvirus 2205 C-type lectin-like EEV protein 374 VARV-GBR46_hind-145 54712 94489641 glycoprotein 1946 Hinden (Middlesex) (Cop-A34R) Variola virus strain United Kingdom Orthopoxvirus 2202 C-type lectin-like EEV protein 374 VARV-GBR47_hig-146 54105 94489841 glycoprotein 1947 Higgins (Staffordshire) (Cop-A34R) Variola virus strain United Kingdom Orthopoxvirus 2200 C-type lectin-like EEV protein 374 VARV-GBR52_but-150 53898 94490045 glycoprotein 1952 Butler (Cop-A34R) Variola virus strain Yugoslavia 1972 Orthopoxvirus 2196 C-type lectin-like EEV protein 374 VARV-YUG72-146 53289 94490250 glycoprotein V72-164 (Cop-A34R) Yaba monkey tumor virus strain Yatapoxvirus 1503 C-type lectin-like EEV protein 374 YMTV-Amano-117 43166 38229286 123R Amano (Cop-A34R) Yaba-like Disease Virus strain Davis Yatapoxvirus 1487 C-type lectin-like EEV protein 374 YLDV-Davis-126 40175 12085106 123R (Cop-A34R)

TABLE 2 Viral Orthologous Clusters V2.0 (VOCs) CD47-like Gene Results Table Genome name Genus Genome id Ortholog Group Name Ortholog Group ID Gene number Gene id Genbank id Genbank name Camelpox virus strain CMS Orthopoxvirus 1493 CD47-like 580 CMLV-CMS-200 41296 19718128 155L Camelpox virus strain M96 Orthopoxvirus 1491 CD47-like 580 CMLV-M96-160 40866 18640392 158 Cowpox virus strain Brighton Red Orthopoxvirus 1496 CD47-like 580 CPXV-BR-181 41880 20178537 175 Cowpox virus strain GRI-90 Orthopoxvirus 1501 CD47-like 580 CPXV-GRI-164 42821 30519532 A40L Cowpox virus strain Germany 91-3 Orthopoxvirus 2214 CD47-like 580 CPXV-GER91-163 56538 90660396 CD47-like putative membrane protein Deerpox virus strain W-1170-84 Unclassified 1516 CD47-like 580 DPV-W1170_84-136 45419 0 139 Deerpox virus strain W-848-83 Unclassified 1515 CD47-like 580 DPV-W848_83-136 45249 62637516 139 Ectromelia virus strain Moscow Orthopoxvirus 1492 CD47-like 580 ECTV-Mos-143 41062 22164744 138 Ectromelia virus strain Naval Orthopoxvirus 1499 CD47-like 580 ECTV-Nav-146 42401 0 160 Goatpox virus strain G20-LKV Capripoxvirus 1514 CD47-like 580 GTPV-G20LKV-127 45087 0 123 Goatpox virus strain Pellor Capripoxvirus 1513 CD47-like 580 GTPV-Pellor-126 44936 0 123 Horsepox virus strain MNR-76 Orthopoxvirus 2230 CD47-like 580 HSPV-MNR76-182 59819 111184349 HSPV160 Lumpy skin disease virus strain Neethling 2490 Capripoxvirus 1488 CD47-like 580 LSDV-Nee-130 40333 15150567 128 Lumpy skin disease virus strain Neethling Capripoxvirus 1497 CD47-like 580 LSDV-NW_LW-132 42066 22595663 128 Warmbaths LW Lumpy skin disease virus strain Neethling vaccine Capripoxvirus 1498 CD47-like 580 LSDV-LW1959-131 42225 22595821 128 LW 1959 Monkeypox Virus strain Walter Reed 267 Orthopoxvirus 1502 CD47-like 580 MPXV-WR267-145 43016 0 144 Monkeypox virus strain COP-58 Orthopoxvirus 1520 CD47-like 580 MPXV-COP58-144 46449 59858950 144 Monkeypox virus strain Congo_2003_358 Orthopoxvirus 1524 CD47-like 580 MPXV-COG_2003_358-155 47214 68449031 159 Monkeypox virus strain Liberia_1970_184 Orthopoxvirus 1525 CD47-like 580 MPXV-LBR_1970_184-152 47411 68449432 159 Monkeypox virus strain Sierra Leone Orthopoxvirus 1521 CD47-like 580 MPXV-SLE-144 46626 58220614 144 Monkeypox virus strain USA_2003_039 Orthopoxvirus 1526 CD47-like 580 MPXV-USA_2003_039-153 47610 68449632 159 Monkeypox virus strain USA_2003_044 Orthopoxvirus 1522 CD47-like 580 MPXV-USA_2003_044-153 46812 68448830 159 Monkeypox virus strain Zaire Orthopoxvirus 1489 CD47-like 580 MPXV-ZAR-153 40514 17975063 A40L Monkeypox virus strain Zaire_1979-005 Orthopoxvirus 1523 CD47-like 580 MPXV-ZAR_1979_005-156 47013 68449233 159 Myxoma virus strain Lausanne Leporipoxvirus 1479 CD47-like 580 MYXV-Lau-133 38557 9633764 m128L Rabbit fibroma virus strain Kasza Leporipoxvirus 1480 CD47-like 580 SFV-Kas-133 38728 9633938 gp128L Rabbitpox virus strain Utrecht Orthopoxvirus 1494 CD47-like 580 RPXV-Utr-148 41510 44971509 146 Sheeppox virus strain A Capripoxvirus 1511 CD47-like 580 SPPV-A-126 44635 0 123 Sheeppox virus strain NISKHI Capripoxvirus 1512 CD47-like 580 SPPV-NISKHI-125 44784 0 123 Sheeppox virus strain TU-V02127 Capripoxvirus 1495 CD47-like 580 SPPV-TU-126 41674 21492580 123 Swinepox virus strain Nebraska 17077-99 Suipoxvirus 1490 CD47-like 580 SWPV-Neb-126 40681 18640211 125 Tanapox virus strain Kenya Yatapoxvirus 3496 CD47-like 580 TANV-KEN-133 67644 146746468 128L Tanapox virus strain isolate TPV-RoC Yatapoxvirus 3497 CD47-like 580 TANV-COD-132 67744 146746624 128L Taterapox virus strain Dahomey 1968 Orthopoxvirus 2195 CD47-like 580 TATV-DAH68-163 53081 113195340 CCD47-like membrane protein Vaccinia virus strain 3737 Orthopoxvirus 1528 CD47-like 580 VACV-3737-164 47952 88900780 158 Vaccinia virus strain Acambis 2000 Orthopoxvirus 2161 CD47-like 580 VACV-Acam2000-171 51227 38349029 173 Vaccinia virus strain Acambis 3 Orthopoxvirus 2162 CD47-like 580 VACV-Acam3-173 51464 37551607 173 Vaccinia virus strain Acambis 3000 Modified Virus Orthopoxvirus 1510 CD47-like 580 VACV-Acam3000-153 44467 47088477 151 Ankara Vaccinia virus strain Copenhagen Orthopoxvirus 1485 CD47-like 580 VACV-Cop-204 39729 335516 A38L Vaccinia virus strain DUKE Orthopoxvirus 2458 CD47-like 580 VACV-DUKE-170 63550 90819822 170 Vaccinia virus strain LC16m8 Orthopoxvirus 1517 CD47-like 580 VACV-LC16m8-218 45671 56713557 m8208L Vaccinia virus strain LC16mO Orthopoxvirus 1518 CD47-like 580 VACV-LC16mO-218 45955 56713841 mO208L Vaccinia virus strain Lister Orthopoxvirus 1519 CD47-like 580 VACV-Lister-218 46239 0 m8208L Vaccinia virus strain Lister_VACV107 Orthopoxvirus 2659 CD47-like 580 VACV-Lister_VACV107-159 64492 88854235 List155 Vaccinia virus strain MVA-I721 Orthopoxvirus 2696 CD47-like 580 VACV-MVA_I721-128 65341 0 151 Vaccinia virus strain Western Reserve Orthopoxvirus 1500 CD47-like 580 VACV-WR-162 42601 66275959 162 Vaccinia virus strain modified vaccinia Ankara Orthopoxvirus 1484 CD47-like 580 VACV-MVA-133 65545 2772738 MVA149L Variola major virus strain Bangladesh 1975 Orthopoxvirus 1481 CD47-like 580 VARV-BGD75maj-151 38912 439062 A41L Variola minor virus strain Garcia 1966 Orthopoxvirus 1482 CD47-like 580 VARV-Gar_1966-156 39109 5830708 A44L Variola virus strain Afghanistan 1970 Variolator 4 Orthopoxvirus 2197 CD47-like 580 VARV-AFG70-152 53496 109724191 membrane protein Variola virus strain Bangladesh 1974 (Shahzaman) Orthopoxvirus 2216 CD47-like 580 VARV-BGD74_shz-152 56944 94484809 membrane protein Variola virus strain Bangladesh 1974 (Solaiman) Orthopoxvirus 2217 CD47-like 580 VARV-BGD74_sol-152 57142 94485007 membrane protein Variola virus strain Bangladesh 1974 (nur islam) Orthopoxvirus 2215 CD47-like 580 VARV-BGD74_nur-152 56746 94484611 membrane protein Variola virus strain Bangladesh 1975 v75-550 Banu Orthopoxvirus 2198 CD47-like 580 VARV-BGD75_Banu-152 53699 109724395 membrane protein Variola virus strain Benin, Dahomey 1968 (v68-59) Orthopoxvirus 2224 CD47-like 580 VARV-BEN68-153 58563 94483793 membrane protein Variola virus strain Botswana 1972 (v72-143) Orthopoxvirus 2225 CD47-like 580 VARV-BWA72-152 58771 94483999 membrane protein Variola virus strain Botswana 1973 (v73-225) Orthopoxvirus 2226 CD47-like 580 VARV-BWA73-152 58973 94484202 membrane protein Variola virus strain Brazil 1966 (v66-39 Sao Paulo) Orthopoxvirus 2227 CD47-like 580 VARV-BRA66-156 59179 94484407 membrane protein Variola virus strain China Horn 1948 Sabin Lab July Orthopoxvirus 2203 CD47-like 580 VARV-CHN48-152 54312 109724597 membrane 1948 protein Variola virus strain Congo 1970 v70-46 Kinshasa Orthopoxvirus 2229 CD47-like 580 VARV-COG70_46-152 59587 109724802 membrane protein Variola virus strain Congo 9 1970 (v74-227 Gispen) Orthopoxvirus 2228 CD47-like 580 VARV-COG70_227-152 59386 94485205 membrane protein Variola virus strain Ethiopia 1972 (Eth16 R14-1X-72 Orthopoxvirus 2231 CD47-like 580 VARV-ETH72_16-153 60026 94485407 membrane Addis) protein Variola virus strain Ethiopia 1972 (Eth17 R14-1X-72 Orthopoxvirus 2232 CD47-like 580 VARV-ETH72_17-153 60229 94485610 membrane Addis) protein Variola virus strain Germany 1958 Heidelberg Orthopoxvirus 2233 CD47-like 580 VARV-DEU58-151 60428 109725005 membrane protein Variola virus strain Guinea 1969 (005) Orthopoxvirus 2234 CD47-like 580 VARV-GIN69-152 60630 94485810 membrane protein Variola virus strain India 1953 (Kali-Muthu-M50 Orthopoxvirus 2238 CD47-like 580 VARV-IND53_mad-152 61442 94486015 membrane Madras) protein Variola virus strain India 1953 (New Delhi) Orthopoxvirus 2239 CD47-like 580 VARV-IND53_ndel-151 61642 94486216 membrane protein Variola virus strain India 1964 7124 Vellore Orthopoxvirus 2240 CD47-like 580 VARV-IND64_vel4-153 61846 109725209 membrane protein Variola virus strain India 1964 7125 Vellore Orthopoxvirus 2241 CD47-like 580 VARV-IND64_vel5-152 62050 109725414 CD47-like membrane protein Variola virus strain India 3 Major 1967 Orthopoxvirus 1483 CD47-like 580 VARV-IND3_1967-150 39312 9627668 A41L Variola virus strain Iran 1972 2602 Tabriz Orthopoxvirus 2235 CD47-like 580 VARV-IRN72-152 60837 109725617 membrane protein Variola virus strain Japan 1946 (Yamada MS-2(A) Orthopoxvirus 2243 CD47-like 580 VARV-JPN46_yam-151 62426 94486419 membrane Tokyo) protein Variola virus strain Japan 1951 (Harper, Masterseed) Orthopoxvirus 2244 CD47-like 580 VARV-JPN51_hrpr-151 62628 94486622 membrane protein Variola virus strain Japan 1951 (Stillwell, Masterseed) Orthopoxvirus 2245 CD47-like 580 VARV-JPN51_stwl-151 62829 94486824 membrane protein Variola virus strain Korea 1947 (Lee, Masterseed) Orthopoxvirus 2236 CD47-like 580 VARV-KOR47-152 61040 94487027 membrane protein Variola virus strain Kuwait 1967 (K1629) Orthopoxvirus 2237 CD47-like 580 VARV-KWT67-152 61242 94487230 membrane protein Variola virus strain Nepal 1973 V73-175 Orthopoxvirus 2221 CD47-like 580 VARV-NPL73-152 57942 109725821 membrane protein Variola virus strain Niger 1969 (001, importation from Orthopoxvirus 2222 CD47-like 580 VARV-NER69-154 58147 94487431 membrane Nigeria) protein Variola virus strain Sierra Leone 1969 (V68-258) Orthopoxvirus 2223 CD47-like 580 VARV-SLE68-153 58355 94488039 membrane protein Variola virus strain Somalia 1977 (V77-1252) Orthopoxvirus 2218 CD47-like 580 VARV-SOM77_1252-152 57340 94488244 membrane protein Variola virus strain Somalia 1977 (V77-1605) Orthopoxvirus 2219 CD47-like 580 VARV-SOM77_1605-152 57540 94488444 membrane protein Variola virus strain Somalia 1977 V77-2479 Orthopoxvirus 2220 CD47-like 580 VARV-SOM77_ali-152 57740 109726228 membrane protein Variola virus strain South Africa 1965 (102 Natal, Orthopoxvirus 2210 CD47-like 580 VARV-ZAF65_102-152 55724 94487636 membrane Ingwavuma) protein Variola virus strain South Africa 1965 (103 Tvaal, Orthopoxvirus 2211 CD47-like 580 VARV-ZAF65_103-152 55925 94487837 membrane Nelspruit) protein Variola virus strain Sudan 1947 (Juba) Orthopoxvirus 2212 CD47-like 580 VARV-SDN47_jub-152 56126 94488644 putative CD47- like membrane protein Variola virus strain Sudan 1947 (Rumbec) Orthopoxvirus 2213 CD47-like 580 VARV-SDN47_rum-152 56326 94488845 membrane protein Variola virus strain Sumatra 1970 V70-222 Orthopoxvirus 2208 CD47-like 580 VARV-SUM70_222-150 55320 109726429 membrane protein Variola virus strain Sumatra 1970 V70-228 Orthopoxvirus 2209 CD47-like 580 VARV-SUM70_228-150 55522 94489044 membrane protein Variola virus strain Syria 1972 V72-199 Orthopoxvirus 2206 CD47-like 580 VARV-SYR72-152 54918 109726634 membrane protein Variola virus strain Tanzania 1965 kembula Orthopoxvirus 2207 CD47-like 580 VARV-TZA65-152 55121 94489245 membrane protein Variola virus strain United Kingdom 1946 Harvey Orthopoxvirus 2204 CD47-like 580 VARV-GBR44_harv-152 54517 94489445 membrane protein Variola virus strain United Kingdom 1946 Hinden Orthopoxvirus 2205 CD47-like 580 VARV-GBR46_hind-151 54718 94489647 membrane (Middlesex) protein Variola virus strain United Kingdom 1947 Higgins Orthopoxvirus 2202 CD47-like 580 VARV-GBR47_hig-152 54111 94489847 membrane (Staffordshire) protein Variola virus strain United Kingdom 1952 Butler Orthopoxvirus 2200 CD47-like 580 VARV-GBR52_but-156 53904 94490051 membrane protein Variola virus strain Yugoslavia 1972 V72-164 Orthopoxvirus 2196 CD47-like 580 VARV-YUG72-152 53295 94490256 membrane protein Yaba monkey tumor virus strain Amano Yatapoxvirus 1503 CD47-like 580 YMTV-Amano-122 43171 38229291 128L Yaba-like Disease Virus strain Davis Yatapoxvirus 1487 CD47-like 580 YLDV-Davis-131 40180 12085111 128L

TABLE 3 Viral Orthologous Clusters V2.0 (VOCs) chemokine binding Gene Results Table Genome Ortholog Genbank Genome name Genus id Group Name Ortholog Group ID Gene number Gene id Genbank id name Bovine papular stomatitis virus strain BV-AR02 Parapoxvirus 1505 Chemokine 557 BPSV-AR02-112 43452 41018864 111 binding protein Bovine papular stomatitis virus strain BV-AR02 Parapoxvirus 1505 Chemokine 557 BPSV-AR02-117 43457 41018869 116 binding protein Camelpox virus strain CMS Orthopoxvirus 1493 Chemokine 557 CMLV-CMS-001 41097 19717930 1L binding protein Camelpox virus strain CMS Orthopoxvirus 1493 Chemokine 557 CMLV-CMS-266 41362 19718194 206R binding protein Camelpox virus strain M96 Orthopoxvirus 1491 Chemokine 557 CMLV-M96-001 40707 18640446 1 binding protein Camelpox virus strain M96 Orthopoxvirus 1491 Chemokine 557 CMLV-M96-213 40919 18640445 211 binding protein Cowpox virus strain Brighton Red Orthopoxvirus 1496 Chemokine 557 CPXV-BR-003 41702 20178372 3 binding protein Cowpox virus strain Brighton Red Orthopoxvirus 1496 Chemokine 557 CPXV-BR-233 41932 20178585 227 binding protein Cowpox virus strain Germany 91-3 Orthopoxvirus 2214 Chemokine 557 CPXV-GER91-001 56376 90660234 CC-chemokine- binding protein binding protein Cowpox virus strain Germany 91-3 Orthopoxvirus 2214 Chemokine 557 CPXV-GER91-219 56594 90660452 CC-chemokine- binding protein binding protein Cowpox virus strain GRI-90 Orthopoxvirus 1501 Chemokine 557 CPXV-GRI-001 42658 30519406 D1L binding protein Cowpox virus strain GRI-90 Orthopoxvirus 1501 Chemokine 557 CPXV-GRI-214 42871 30519582 I5R binding protein Ectromelia virus strain Moscow Orthopoxvirus 1492 Chemokine 557 ECTV-Mos-001 40920 22164608 1 binding protein Ectromelia virus strain Moscow Orthopoxvirus 1492 Chemokine 557 ECTV-Mos-177 41096 22164607 172 binding protein Ectromelia virus strain Naval Orthopoxvirus 1499 Chemokine 557 ECTV-Nav-001 42256 0 1_179 binding protein Ectromelia virus strain Naval Orthopoxvirus 1499 Chemokine 557 ECTV-Nav-182 42437 0 E1 binding protein Horsepox virus strain MNR-76 Orthopoxvirus 2230 Chemokine 557 HSPV-MNR76-002 59639 111184169 HSPV002 binding protein Horsepox virus strain MNR-76 Orthopoxvirus 2230 Chemokine 557 HSPV-MNR76-235 59872 111184402 HSPV206 binding protein Monkeypox virus strain Congo_2003_358 Orthopoxvirus 1524 Chemokine 557 MPXV-COG_2003_358-001 47060 68448877 1 binding protein Monkeypox virus strain Congo_2003_358 Orthopoxvirus 1524 Chemokine 557 MPXV-COG_2003_358-200 47259 68449076 206 binding protein Monkeypox virus strain COP-58 Orthopoxvirus 1520 Chemokine 557 MPXV-COP58-001 46306 59858807 1 binding protein Monkeypox virus strain COP-58 Orthopoxvirus 1520 Chemokine 557 MPXV-COP58-177 46482 59858983 177 binding protein Monkeypox virus strain Liberia_1970_184 Orthopoxvirus 1525 Chemokine 557 MPXV-LBR_1970_184-001 47260 68449281 1 binding protein Monkeypox virus strain Liberia_1970_184 Orthopoxvirus 1525 Chemokine 557 MPXV-LBR_1970_184-198 47457 68449478 206 binding protein Monkeypox virus strain Sierra Leone Orthopoxvirus 1521 Chemokine 557 MPXV-SLE-001 46483 58220471 1 binding protein Monkeypox virus strain Sierra Leone Orthopoxvirus 1521 Chemokine 557 MPXV-SLE-177 46659 58220647 177 binding protein Monkeypox virus strain USA_2003_039 Orthopoxvirus 1526 Chemokine 557 MPXV-USA_2003_039-001 47458 68449480 1 binding protein Monkeypox virus strain USA_2003_039 Orthopoxvirus 1526 Chemokine 557 MPXV-USA_2003_039-198 47655 68449677 206 binding protein Monkeypox virus strain USA_2003_044 Orthopoxvirus 1522 Chemokine 557 MPXV-USA_2003_044-001 46660 68448678 1 binding protein Monkeypox virus strain USA_2003_044 Orthopoxvirus 1522 Chemokine 557 MPXV-USA_2003_044-198 46857 68448875 206 binding protein Monkeypox Virus strain Walter Reed 267 Orthopoxvirus 1502 Chemokine 557 MPXV-WR267-001 42872 0 1 binding protein Monkeypox Virus strain Walter Reed 267 Orthopoxvirus 1502 Chemokine 557 MPXV-WR267-178 43049 0 177 binding protein Monkeypox virus strain Zaire Orthopoxvirus 1489 Chemokine 557 MPXV-ZAR-001 40362 17974914 J1L binding protein Monkeypox virus strain Zaire Orthopoxvirus 1489 Chemokine 557 MPXV-ZAR-194 40555 17975104 J3R binding protein Monkeypox virus strain Zaire_1979-005 Orthopoxvirus 1523 Chemokine 557 MPXV-ZAR_1979_005-001 46858 68449078 1 binding protein Monkeypox virus strain Zaire_1979-005 Orthopoxvirus 1523 Chemokine 557 MPXV-ZAR_1979_005-202 47059 68449279 206 binding protein Myxoma virus strain Lausanne Leporipoxvirus 1479 Chemokine 557 MYXV-Lau-002 38427 9633793 m001L binding protein Myxoma virus strain Lausanne Leporipoxvirus 1479 Chemokine 557 MYXV-Lau-170 38594 9633634 M_T1 binding protein Orf virus strain OV-IA82 Parapoxvirus 1507 Chemokine 557 ORFV-IA82-112 43913 41018599 109 binding protein Orf virus strain OV-IA82 Parapoxvirus 1507 Chemokine 557 ORFV-IA82-117 43918 41018604 114 binding protein Orf virus strain NZ2 Parapoxvirus 1527 Chemokine 557 ORFV-NZ2-111 47766 74230825 112 binding protein Orf virus strain NZ2 Parapoxvirus 1527 Chemokine 557 ORFV-NZ2-116 47771 74230830 117 binding protein Orf virus strain NZ2 Patent WO03006654 Parapoxvirus 1504 Chemokine 557 ORFV-NZ2_Pat-117 43306 32167506 114 binding protein Orf virus strain NZ2 Patent WO03006654 Parapoxvirus 1504 Chemokine 557 ORFV-NZ2_Pat-123 43312 32167512 120 binding protein Orf virus strain OV-SA00 Parapoxvirus 1508 Chemokine 557 ORFV-SA00-112 44049 41018732 109 binding protein Orf virus strain OV-SA00 Parapoxvirus 1508 Chemokine 557 ORFV-SA00-117 44054 41018737 114 binding protein Rabbitpox virus strain Utrecht Orthopoxvirus 1494 Chemokine 557 RPXV-Utr-001 41363 44971364 1 binding protein Rabbitpox virus strain Utrecht Orthopoxvirus 1494 Chemokine 557 RPXV-Utr-186 41548 44971547 184 binding protein Rabbit fibroma virus strain Kasza Leporipoxvirus 1480 Chemokine 557 SFV-Kas-001 38596 9633810 gp001L binding protein Rabbit fibroma virus strain Kasza Leporipoxvirus 1480 Chemokine 557 SFV-Kas-166 38761 9633971 s001R binding protein Taterapox virus strain Dahomey 1968 Orthopoxvirus 2195 Chemokine 557 TATV-DAH68-001 52919 113195178 chemokine- binding protein binding protein Taterapox virus strain Dahomey 1968 Orthopoxvirus 2195 Chemokine 557 TATV-DAH68-002 52920 113195179 chemokine- binding protein binding protein Taterapox virus strain Dahomey 1968 Orthopoxvirus 2195 Chemokine 557 TATV-DAH68-003 52921 113195180 chemokine- binding protein binding protein Taterapox virus strain Dahomey 1968 Orthopoxvirus 2195 Chemokine 557 TATV-DAH68-223 53141 113195400 chemokine- binding protein binding protein Taterapox virus strain Dahomey 1968 Orthopoxvirus 2195 Chemokine 557 TATV-DAH68-224 53142 113195401 chemokine- binding protein binding protein Taterapox virus strain Dahomey 1968 Orthopoxvirus 2195 Chemokine 557 TATV-DAH68-225 53143 113195402 chemokine- binding protein binding protein Vaccinia virus strain 3737 Orthopoxvirus 1528 Chemokine 557 VACV-3737-001 47789 88900617 1 binding protein Vaccinia virus strain Acambis 2000 Orthopoxvirus 2161 Chemokine 557 VACV-Acam2000-001 51057 38348859 1 binding protein Vaccinia virus strain Acambis 2000 Orthopoxvirus 2161 Chemokine 557 VACV-Acam2000-235 51291 38349093 241 binding protein Vaccinia virus strain Acambis 3 Orthopoxvirus 2162 Chemokine 557 VACV-Acam3-001 51292 37551436 1 binding protein Vaccinia virus strain Acambis 3 Orthopoxvirus 2162 Chemokine 557 VACV-Acam3-229 51520 37551663 241 binding protein Vaccinia virus strain Acambis 3000 Modified Virus Ankara Orthopoxvirus 1510 Chemokine 557 VACV-Acam3000-001 44315 47088327 1 binding protein Vaccinia virus strain Acambis 3000 Modified Virus Ankara Orthopoxvirus 1510 Chemokine 557 VACV-Acam3000-195 44509 47088519 193 binding protein Vaccinia virus strain Copenhagen Orthopoxvirus 1485 Chemokine 557 VACV-Cop-001 39526 335318 C23L binding protein Vaccinia virus strain Copenhagen Orthopoxvirus 1485 Chemokine 557 VACV-Cop-265 39790 335577 B29R binding protein Vaccinia virus strain DUKE Orthopoxvirus 2458 Chemokine 557 VACV-DUKE-001 63381 90819653 1 binding protein Vaccinia virus strain DUKE Orthopoxvirus 2458 Chemokine 557 VACV-DUKE-225 63605 90819877 225 binding protein Vaccinia virus strain LC16m8 Orthopoxvirus 1517 Chemokine 557 VACV-LC16m8-001 45454 56713344 m8LTR10L binding protein Vaccinia virus strain LC16m8 Orthopoxvirus 1517 Chemokine 557 VACV-LC16m8-282 45735 56713621 m8RTR10R binding protein Vaccinia virus strain LC16mO Orthopoxvirus 1518 Chemokine 557 VACV-LC16mO-001 45738 56713628 mOLTR10L binding protein Vaccinia virus strain LC16mO Orthopoxvirus 1518 Chemokine 557 VACV-LC16mO-282 46019 56713905 mORTR10R binding protein Vaccinia virus strain Lister Orthopoxvirus 1519 Chemokine 557 VACV-Lister-001 46022 0 m8LTR10L binding protein Vaccinia virus strain Lister Orthopoxvirus 1519 Chemokine 557 VACV-Lister-282 46303 0 m8RTR10R binding protein Vaccinia virus strain Lister_VACV107 Orthopoxvirus 2659 Chemokine 557 VACV-Lister_VACV107-001 64334 88854292 List001 binding protein Vaccinia virus strain Lister_VACV107 Orthopoxvirus 2659 Chemokine 557 VACV-Lister_VACV107-205 64538 119352441 List201 binding protein Vaccinia virus strain MVA-I721 Orthopoxvirus 2696 Chemokine 557 VACV-MVA_I721-054 65268 0 193 binding protein Vaccinia virus strain Western Reserve Orthopoxvirus 1500 Chemokine 557 VACV-WR-001 42438 66275798 1 binding protein Vaccinia virus strain Western Reserve Orthopoxvirus 1500 Chemokine 557 VACV-WR-218 42657 66276015 218 binding protein Variola virus strain Afghanistan 1970 Variolator 4 Orthopoxvirus 2197 Chemokine 557 VARV-AFG70-203 53547 109724242 CC-chemokine- binding protein binding protein Variola virus strain Benin, Dahomey 1968 (v68-59) Orthopoxvirus 2224 Chemokine 557 VARV-BEN68-208 58618 94483845 CC-chemokine- binding protein binding protein Variola virus strain Bangladesh 1974 (nur islam) Orthopoxvirus 2215 Chemokine 557 VARV-BGD74_nur-198 56792 94484656 CC-chemokine- binding protein binding protein Variola virus strain Bangladesh 1974 (Shahzaman) Orthopoxvirus 2216 Chemokine 557 VARV-BGD74_shz-198 56990 94484854 CC-chemokine- binding protein binding protein Variola virus strain Bangladesh 1974 (Solaiman) Orthopoxvirus 2217 Chemokine 557 VARV-BGD74_sol-198 57188 94485052 CC-chemokine- binding protein binding protein Variola virus strain Bangladesh 1975 v75-550 Banu Orthopoxvirus 2198 Chemokine 557 VARV-BGD75_Banu-201 53748 109724444 CC-chemokine- binding protein binding protein Variola major virus strain Bangladesh 1975 Orthopoxvirus 1481 Chemokine 557 VARV-BGD75maj-192 38953 439103 G3R binding protein Variola virus strain Brazil 1966 (v66-39 Sao Paulo) Orthopoxvirus 2227 Chemokine 557 VARV-BRA66-210 59233 94484458 CC-chemokine- binding protein binding protein Variola virus strain Botswana 1972 (v72-143) Orthopoxvirus 2225 Chemokine 557 VARV-BWA72-202 58821 94484049 CC-chemokine- binding protein binding protein Variola virus strain Botswana 1973 (v73-225) Orthopoxvirus 2226 Chemokine 557 VARV-BWA73-202 59023 94484251 CC-chemokine- binding protein binding protein Variola virus strain China Horn 1948 Sabin Lab July 1948 Orthopoxvirus 2203 Chemokine 557 VARV-CHN48-204 54364 109724648 CC-chemokine- binding protein binding protein Variola virus strain Congo 9 1970 (v74-227 Gispen) Orthopoxvirus 2228 Chemokine 557 VARV-COG70_227-201 59435 94485253 CC-chemokine- binding protein binding protein Variola virus strain Congo 1970 v70-46 Kinshasa Orthopoxvirus 2229 Chemokine 557 VARV-COG70_46-202 59637 109724853 CC-chemokine- binding protein binding protein Variola virus strain Germany 1958 Heidelberg Orthopoxvirus 2233 Chemokine 557 VARV-DEU58-201 60478 109725055 CC-chemokine- binding protein binding protein Variola virus strain Ethiopia 1972 (Eth16 R14-1X-72 Addis) Orthopoxvirus 2231 Chemokine 557 VARV-ETH72_16-203 60076 94485456 CC-chemokine- binding protein binding protein Variola virus strain Ethiopia 1972 (Eth17 R14-1X-72 Addis) Orthopoxvirus 2232 Chemokine 557 VARV-ETH72_17-201 60277 94485658 CC-chemokine- binding protein binding protein Variola virus strain United Kingdom 1946 Harvey Orthopoxvirus 2204 Chemokine 557 VARV-GBR44_harv-202 54567 94489495 CC-chemokine- binding protein binding protein Variola virus strain United Kingdom 1946 Hinden (Middlesex) Orthopoxvirus 2205 Chemokine 557 VARV-GBR46_hind-199 54766 94489694 CC-chemokine- binding protein binding protein Variola virus strain United Kingdom 1947 Higgins (Staffordshire) Orthopoxvirus 2202 Chemokine 557 VARV-GBR47_hig-201 54160 94489895 CC-chemokine- binding protein binding protein Variola virus strain United Kingdom 1952 Butler Orthopoxvirus 2200 Chemokine 557 VARV-GBR52_but-210 53958 94490102 CC-chemokine- binding protein binding protein Variola virus strain Guinea 1969 (005) Orthopoxvirus 2234 Chemokine 557 VARV-GIN69-206 60684 94485861 CC-chemokine- binding protein binding protein Variola minor virus strain Garcia 1966 Orthopoxvirus 1482 Chemokine 557 VARV-Gar_1966-208 39161 5830760 G3R binding protein Variola virus strain India 3 Major 1967 Orthopoxvirus 1483 Chemokine 557 VARV-IND3_1967-200 39362 9627718 G5R binding protein Variola virus strain India 1953 (Kali-Muthu-M50 Madras) Orthopoxvirus 2238 Chemokine 557 VARV-IND53_mad-201 61491 94486064 CC-chemokine- binding protein binding protein Variola virus strain India 1953 (New Delhi) Orthopoxvirus 2239 Chemokine 557 VARV-IND53_ndel-201 61692 94486266 CC-chemokine- binding protein binding protein Variola virus strain India 1964 7124 Vellore Orthopoxvirus 2240 Chemokine 557 VARV-IND64_vel4-205 61898 109725261 CC-chemokine- binding protein binding protein Variola virus strain India 1964 7125 Vellore Orthopoxvirus 2241 Chemokine 557 VARV-IND64_vel5-203 62101 109725464 CC-chemokine- binding protein binding protein Variola virus strain Iran 1972 2602 Tabriz Orthopoxvirus 2235 Chemokine 557 VARV-IRN72-203 60888 109725668 CC-chemokine- binding protein binding protein Variola virus strain Japan 1946 (Yamada MS-2(A) Tokyo) Orthopoxvirus 2243 Chemokine 557 VARV-JPN46_yam-201 62476 94486469 CC-chemokine- binding protein binding protein Variola virus strain Japan 1951 (Harper, Masterseed) Orthopoxvirus 2244 Chemokine 557 VARV-JPN51_hrpr-200 62677 94486671 CC-chemokine- binding protein binding protein Variola virus strain Japan 1951 (Stillwell, Masterseed) Orthopoxvirus 2245 Chemokine 557 VARV-JPN51_stwl-201 62879 94486873 CC-chemokine- binding protein binding protein Variola virus strain Korea 1947 (Lee, Masterseed) Orthopoxvirus 2236 Chemokine 557 VARV-KOR47-202 61090 94487077 CC-chemokine- binding protein binding protein Variola virus strain Kuwait 1967 (K1629) Orthopoxvirus 2237 Chemokine 557 VARV-KWT67-200 61290 94487277 CC-chemokine- binding protein binding protein Variola virus strain Niger 1969 (001, importation from Nigeria) Orthopoxvirus 2222 Chemokine 557 VARV-NER69-208 58201 94487482 CC-chemokine- binding protein binding protein Variola virus strain Nepal 1973 V73-175 Orthopoxvirus 2221 Chemokine 557 VARV-NPL73-202 57992 109725870 CC-chemokine- binding protein binding protein Variola virus strain Sudan 1947 (Juba) Orthopoxvirus 2212 Chemokine 557 VARV-SDN47_jub-200 56174 94488692 CC-chemokine- binding protein binding protein Variola virus strain Sudan 1947 (Rumbec) Orthopoxvirus 2213 Chemokine 557 VARV-SDN47_rum-201 56375 94488893 CC-chemokine- binding protein binding protein Variola virus strain Sierra Leone 1969 (V68-258) Orthopoxvirus 2223 Chemokine 557 VARV-SLE68-207 58409 94488090 CC-chemokine- binding protein binding protein Variola virus strain Somalia 1977 (V77-1252) Orthopoxvirus 2218 Chemokine 557 VARV-SOM77_1252-200 57388 94488291 CC-chemokine- binding protein binding protein Variola virus strain Somalia 1977 (V77-1605) Orthopoxvirus 2219 Chemokine 557 VARV-SOM77_1605-200 57588 94488491 CC-chemokine- binding protein binding protein Variola virus strain Somalia 1977 V77-2479 Orthopoxvirus 2220 Chemokine 557 VARV-SOM77_ali-202 57790 109726278 CC-chemokine- binding protein binding protein Variola virus strain Sumatra 1970 V70-222 Orthopoxvirus 2208 Chemokine 557 VARV-SUM70_222-201 55371 109726480 CC-chemokine- binding protein binding protein Variola virus strain Sumatra 1970 V70-228 Orthopoxvirus 2209 Chemokine 557 VARV-SUM70_228-199 55571 94489092 CC-chemokine- binding protein binding protein Variola virus strain Syria 1972 V72-199 Orthopoxvirus 2206 Chemokine 557 VARV-SYR72-203 54969 109726685 CC-chemokine- binding protein binding protein Variola virus strain Tanzania 1965 kembula Orthopoxvirus 2207 Chemokine 557 VARV-TZA65-201 55170 94489292 CC-chemokine- binding protein binding protein Variola virus strain Yugoslavia 1972 V72-164 Orthopoxvirus 2196 Chemokine 557 VARV-YUG72-201 53344 94490305 CC-chemokine- binding protein binding protein Variola virus strain South Africa 1965 (102 Natal, Ingwavuma) Orthopoxvirus 2210 Chemokine 557 VARV-ZAF65_102-201 55773 94487684 CC-chemokine- binding protein binding protein Variola virus strain South Africa 1965 (103 Tvaal, Nelspruit) Orthopoxvirus 2211 Chemokine 557 VARV-ZAF65_103-201 55974 94487886 CC-chemokine- binding protein binding protein

TABLE 4 Viral Orthologous Clusters V2.0 (VOCs) complement binding protein Gene Results Table Genome name Genus Genome id Ortholog Group Name Ortholog Group ID Gene number Gene id Genbank id Genbank name Camelpox virus strain CMS Orthopoxvirus 1493 Complement binding (secreted) 604 CMLV-CMS-025 41121 19717954 23L Camelpox virus strain CMS Orthopoxvirus 1493 Complement control/CD46/EEV 591 CMLV-CMS-230 41326 19718158 178R Camelpox virus strain M96 Orthopoxvirus 1491 Complement binding (secreted) 604 CMLV-M96-023 40729 18640257 23 Camelpox virus strain M96 Orthopoxvirus 1491 Complement control/CD46/EEV 591 CMLV-M96-183 40889 18640415 181 Cowpox virus strain Brighton Red Orthopoxvirus 1496 Complement binding (secreted) 604 CPXV-BR-034 41733 20178402 34 Cowpox virus strain Brighton Red Orthopoxvirus 1496 Complement control/CD46/EEV 591 CPXV-BR-205 41904 20178559 199 Cowpox virus strain GRI-90 Orthopoxvirus 1501 Complement binding (secreted) 604 CPXV-GRI-031 42688 1808620 C17L Cowpox virus strain GRI-90 Orthopoxvirus 1501 Complement control/CD46/EEV 591 CPXV-GRI-187 42844 30519555 B4R Cowpox virus strain Germany 91-3 Orthopoxvirus 2214 Complement binding (secreted) 604 CPXV-GER91-032 56407 90660265 secreted protein Cowpox virus strain Germany 91-3 Orthopoxvirus 2214 Complement control/CD46/EEV 591 CPXV-GER91-186 56561 90660419 EEV membrane glycoprotein Deerpox virus strain W-1170-84 Unclassified 1516 Complement control/CD46/EEV 591 DPV-W1170_84-155 45438 0 156 Deerpox virus strain W-848-83 Unclassified 1515 Complement control/CD46/EEV 591 DPV-W848_83-154 45267 62637533 156 Ectromelia virus strain Moscow Orthopoxvirus 1492 Complement binding (secreted) 604 ECTV-Mos-018 40937 22164624 17 Ectromelia virus strain Moscow Orthopoxvirus 1492 Complement control/CD46/EEV 591 ECTV-Mos-160 41079 22164590 155 Ectromelia virus strain Naval Orthopoxvirus 1499 Complement binding (secreted) 604 ECTV-Nav-018 42273 0 28 Ectromelia virus strain Naval Orthopoxvirus 1499 Complement control/CD46/EEV 591 ECTV-Nav-165 42420 0 182 Goatpox virus strain G20-LKV Capripoxvirus 1514 Complement control/CD46/EEV 591 GTPV-G20LKV-140 45100 0 134 Goatpox virus strain Pellor Capripoxvirus 1513 Complement control/CD46/EEV 591 GTPV-Pellor-138 44948 0 134 Horsepox virus strain MNR-76 Orthopoxvirus 2230 Complement binding (secreted) 604 HSPV-MNR76-042 59679 111184209 HSPV028 Horsepox virus strain MNR-76 Orthopoxvirus 2230 Complement control/CD46/EEV 591 HSPV-MNR76-207 59844 111184374 HSPV182 Lumpy skin disease virus strain Neethling Capripoxvirus 1488 Complement control/CD46/EEV 591 LSDV-Nee-143 40346 15150580 141 2490 Lumpy skin disease virus strain Neethling Capripoxvirus 1497 Complement control/CD46/EEV 591 LSDV-NW_LW-145 42079 22595676 141 Warmbaths LW Lumpy skin disease virus strain Neethling Capripoxvirus 1498 Complement control/CD46/EEV 591 LSDV-LW1959-145 42239 22595835 141 vaccine LW 1959 Monkeypox Virus strain Walter Reed 267 Orthopoxvirus 1502 Complement control/CD46/EEV 591 MPXV-WR267-160 43031 0 159 Monkeypox virus strain COP-58 Orthopoxvirus 1520 Complement control/CD46/EEV 591 MPXV-COP58-159 46464 59858965 159 Monkeypox virus strain Congo_2003_358 Orthopoxvirus 1524 Complement binding (secreted) 604 MPXV-COG_2003_358-019 47078 68448895 22 Monkeypox virus strain Congo_2003_358 Orthopoxvirus 1524 Complement control/CD46/EEV 591 MPXV-COG_2003_358-173 47232 68449049 180 Monkeypox virus strain Liberia_1970_184 Orthopoxvirus 1525 Complement control/CD46/EEV 591 MPXV-LBR_1970_184-172 47431 68449452 180 Monkeypox virus strain Sierra Leone Orthopoxvirus 1521 Complement control/CD46/EEV 591 MPXV-SLE-159 46641 58220629 159 Monkeypox virus strain USA_2003_039 Orthopoxvirus 1526 Complement control/CD46/EEV 591 MPXV-USA_2003_039-173 47630 68449652 180 Monkeypox virus strain USA_2003_044 Orthopoxvirus 1522 Complement control/CD46/EEV 591 MPXV-USA_2003_044-173 46832 68448850 180 Monkeypox virus strain Zaire Orthopoxvirus 1489 Complement binding (secreted) 604 MPXV-ZAR-017 40378 17974930 D14L Monkeypox virus strain Zaire Orthopoxvirus 1489 Complement control/CD46/EEV 591 MPXV-ZAR-170 40531 17975080 B6R Monkeypox virus strain Zaire_1979-005 Orthopoxvirus 1523 Complement binding (secreted) 604 MPXV-ZAR_1979_005-019 46876 68449096 22 Monkeypox virus strain Zaire_1979-005 Orthopoxvirus 1523 Complement control/CD46/EEV 591 MPXV-ZAR_1979_005-174 47031 68449251 180 Myxoma virus strain Lausanne Leporipoxvirus 1479 Complement control/CD46/EEV 591 MYXV-Lau-149 38573 9633780 m144R Rabbit fibroma virus strain Kasza Leporipoxvirus 1480 Complement control/CD46/EEV 591 SFV-Kas-146 38741 9633950 gp144R Rabbitpox virus strain Utrecht Orthopoxvirus 1494 Complement binding (secreted) 604 RPXV-Utr-017 41379 44971380 17 Rabbitpox virus strain Utrecht Orthopoxvirus 1494 Complement control/CD46/EEV 591 RPXV-Utr-169 41531 44971530 167 Sheeppox virus strain A Capripoxvirus 1511 Complement control/CD46/EEV 591 SPPV-A-137 44646 0 134 Sheeppox virus strain NISKHI Capripoxvirus 1512 Complement control/CD46/EEV 591 SPPV-NISKHI-136 44795 0 134 Sheeppox virus strain TU-V02127 Capripoxvirus 1495 Complement control/CD46/EEV 591 SPPV-TU-138 41686 21492591 134 Swinepox virus strain Nebraska 17077-99 Suipoxvirus 1490 Complement control/CD46/EEV 591 SWPV-Neb-140 40695 18640225 139 Tanapox virus strain Kenya Yatapoxvirus 3496 Complement control/CD46/EEV 591 TANV-KEN-149 67676 146746484 144R Tanapox virus strain isolate TPV-RoC Yatapoxvirus 3497 Complement control/CD46/EEV 591 TANV-COD-148 67760 146746640 144R Taterapox virus strain Dahomey 1968 Orthopoxvirus 2195 Complement binding (secreted) 604 TATV-DAH68-026 52944 113195203 secreted protein Taterapox virus strain Dahomey 1968 Orthopoxvirus 2195 Complement control/CD46/EEV 591 TATV-DAH68-188 53106 113195365 EEV membrane glycoprotein Vaccinia virus strain 3737 Orthopoxvirus 1528 Complement binding (secreted) 604 VACV-3737-027 47815 88900643 24 Vaccinia virus strain 3737 Orthopoxvirus 1528 Complement control/CD46/EEV 591 VACV-3737-188 47976 88900804 177 Vaccinia virus strain Acambis 2000 Orthopoxvirus 2161 Complement binding (secreted) 604 VACV-Acam2000-034 51090 38348892 34 Vaccinia virus strain Acambis 2000 Orthopoxvirus 2161 Complement control/CD46/EEV 591 VACV-Acam2000-196 51252 38349054 198 Vaccinia virus strain Acambis 3 Orthopoxvirus 2162 Complement binding (secreted) 604 VACV-Acam3-034 51325 37551468 34 Vaccinia virus strain Acambis 3 Orthopoxvirus 2162 Complement control/CD46/EEV 591 VACV-Acam3-198 51489 37551632 198 Vaccinia virus strain Acambis 3000 Orthopoxvirus 1510 Complement control/CD46/EEV 591 VACV-Acam3000-175 44489 47088499 173 Modified Virus Ankara Vaccinia virus strain Copenhagen Orthopoxvirus 1485 Complement binding (secreted) 604 VACV-Cop-028 39553 335345 C3L Vaccinia virus strain Copenhagen Orthopoxvirus 1485 Complement control/CD46/EEV 591 VACV-Cop-237 39762 335549 B5R Vaccinia virus strain DUKE Orthopoxvirus 2458 Complement binding (secreted) 604 VACV-DUKE-034 63414 90819686 34 Vaccinia virus strain DUKE Orthopoxvirus 2458 Complement control/CD46/EEV 591 VACV-DUKE-196 63576 90819848 196 Vaccinia virus strain LC16m8 Orthopoxvirus 1517 Complement binding (secreted) 604 VACV-LC16m8-036 45489 56713377 m8025L Vaccinia virus strain LC16m8 Orthopoxvirus 1517 Complement control/CD46/EEV 591 VACV-LC16m8-253 45706 56713592 m8243R Vaccinia virus strain LC16mO Orthopoxvirus 1518 Complement binding (secreted) 604 VACV-LC16mO-036 45773 56713661 mO025L Vaccinia virus strain LC16mO Orthopoxvirus 1518 Complement control/CD46/EEV 591 VACV-LC16mO-253 45990 56713876 mO243R Vaccinia virus strain Lister Orthopoxvirus 1519 Complement binding (secreted) 604 VACV-Lister-036 46057 0 m8025L Vaccinia virus strain Lister Orthopoxvirus 1519 Complement control/CD46/EEV 591 VACV-Lister-253 46274 0 m8243R Vaccinia virus strain Lister_VACV107 Orthopoxvirus 2659 Complement binding (secreted) 604 VACV-Lister_VACV107-026 64359 88854053 List022 Vaccinia virus strain Lister_VACV107 Orthopoxvirus 2659 Complement control/CD46/EEV 591 VACV-Lister_VACV107-186 64519 88854268 List182 Vaccinia virus strain MVA-I721 Orthopoxvirus 2696 Complement control/CD46/EEV 591 VACV-MVA_I721-095 65309 0 173 Vaccinia virus strain Western Reserve Orthopoxvirus 1500 Complement binding (secreted) 604 VACV-WR-025 42462 66275822 25 Vaccinia virus strain Western Reserve Orthopoxvirus 1500 Complement control/CD46/EEV 591 VACV-WR-187 42626 66275984 187 Vaccinia virus strain modified vaccinia Orthopoxvirus 1484 Complement control/CD46/EEV 591 VACV-MVA-151 65563 2772808 MVA173R Ankara Variola major virus strain Bangladesh Orthopoxvirus 1481 Complement binding (secreted) 604 VARV-BGD75maj-015 38776 438930 D15L 1975 Variola major virus strain Bangladesh Orthopoxvirus 1481 Complement control/CD46/EEV 591 VARV-BGD75maj-173 38934 439084 B6R 1975 Variola minor virus strain Garcia 1966 Orthopoxvirus 1482 Complement binding (secreted) 604 VARV-Gar_1966-018 38971 5830573 B18L Variola minor virus strain Garcia 1966 Orthopoxvirus 1482 Complement control/CD46/EEV 591 VARV-Gar_1966-185 39138 5830737 H7R Variola virus strain Afghanistan 1970 Orthopoxvirus 2197 Complement binding (secreted) 604 VARV-AFG70-015 53359 109724054 secreted protein Variolator 4 Variola virus strain Afghanistan 1970 Orthopoxvirus 2197 Complement control/CD46/EEV 591 VARV-AFG70-178 53522 109724217 glycoprotein Variolator 4 Variola virus strain Bangladesh 1974 Orthopoxvirus 2216 Complement binding (secreted) 604 VARV-BGD74_shz-015 56807 94484672 secreted protein (Shahzaman) Variola virus strain Bangladesh 1974 Orthopoxvirus 2216 Complement control/CD46/EEV 591 VARV-BGD74_shz-177 56969 94484834 glycoprotein (Shahzaman) Variola virus strain Bangladesh 1974 Orthopoxvirus 2217 Complement binding (secreted) 604 VARV-BGD74_sol-015 57005 94484870 secreted protein (Solaiman) Variola virus strain Bangladesh 1974 Orthopoxvirus 2217 Complement control/CD46/EEV 591 VARV-BGD74_sol-177 57167 94485032 glycoprotein (Solaiman) Variola virus strain Bangladesh 1974 (nur Orthopoxvirus 2215 Complement binding (secreted) 604 VARV-BGD74_nur-015 56609 94484475 secreted protein islam) Variola virus strain Bangladesh 1974 (nur Orthopoxvirus 2215 Complement control/CD46/EEV 591 VARV-BGD74_nur-177 56771 94484636 glycoprotein islam) Variola virus strain Bangladesh 1975 v75- Orthopoxvirus 2198 Complement binding (secreted) 604 VARV-BGD75_Banu-015 53562 109724258 secreted protein 550 Banu Variola virus strain Bangladesh 1975 v75- Orthopoxvirus 2198 Complement control/CD46/EEV 591 VARV-BGD75_Banu-177 53724 109724420 glycoprotein 550 Banu Variola virus strain Benin, Dahomey 1968 Orthopoxvirus 2224 Complement binding (secreted) 604 VARV-BEN68-017 58427 94483658 secreted protein (v68-59) Variola virus strain Benin, Dahomey 1968 Orthopoxvirus 2224 Complement control/CD46/EEV 591 VARV-BEN68-182 58592 94483822 glycoprotein (v68-59) Variola virus strain Botswana 1972 (v72- Orthopoxvirus 2225 Complement binding (secreted) 604 VARV-BWA72-015 58634 94483862 secreted protein 143) Variola virus strain Botswana 1972 (v72- Orthopoxvirus 2225 Complement control/CD46/EEV 591 VARV-BWA72-178 58797 94484025 glycoprotein 143) Variola virus strain Botswana 1973 (v73- Orthopoxvirus 2226 Complement binding (secreted) 604 VARV-BWA73-015 58836 94484065 secreted protein 225) Variola virus strain Botswana 1973 (v73- Orthopoxvirus 2226 Complement contro/CD46/EEV 591 VARV-BWA73-178 58999 94484228 glycoprotein 225) Variola virus strain Brazil 1966 (v66-39 Orthopoxvirus 2227 Complement binding (secreted) 604 VARV-BRA66-019 59042 94484271 secreted protein Sao Paulo) Variola virus strain Brazil 1966 (v66-39 Orthopoxvirus 2227 Complement control/CD46/EEV 591 VARV-BRA66-185 59208 94484436 glycoprotein Sao Paulo) Variola virus strain China Hom 1948 Orthopoxvirus 2203 Complement binding (secreted) 604 VARV-CHN48-015 54175 109724460 secreted protein Sabin Lab July 1948 Variola virus strain China Hom 1948 Orthopoxvirus 2203 Complement control/CD46/EEV 591 VARV-CHN48-179 54339 109724624 glycoprotein Sabin Lab July 1948 Variola virus strain Congo 1970 v70-46 Orthopoxvirus 2229 Complement binding (secreted) 604 VARV-COG70_46-015 59450 109724665 secreted protein Kinshasa Variola virus strain Congo 1970 v70-46 Orthopoxvirus 2229 Complement control/CD46/EEV 591 VARV-COG70_46-177 59612 109724828 glycoprotein Kinshasa Variola virus strain Congo 9 1970 (v74- Orthopoxvirus 2228 Complement binding (secreted) 604 VARV-COG70_227-015 59249 94485068 secreted protein 227 Gispen) Variola virus strain Congo 9 1970 (v74- Orthopoxvirus 2228 Complement control/CD46/EEV 591 VARV-COG70_227-178 59412 94485231 glycoprotein 227 Gispen) Variola virus strain Ethiopia 1972 (Eth16 Orthopoxvirus 2231 Complement binding (secreted) 604 VARV-ETH72_16-015 59888 94485269 secreted protein R14-1X-72 Addis) Variola virus strain Ethiopia 1972 (Eth16 Orthopoxvirus 2231 Complement control/CD46/EEV 591 VARV-ETH72_16-179 60052 94485433 glycoprotein R14-1X-72 Addis) Variola virus strain Ethiopia 1972 (Eth17 Orthopoxvirus 2232 Complement binding (secreted) 604 VARV-ETH72_17-015 60091 94485472 secreted protein R14-1X-72 Addis) Variola virus strain Ethiopia 1972 (Eth17 Orthopoxvirus 2232 Complement control/CD46/EEV 591 VARV-ETH72_17-179 60255 94485636 glycoprotein R14-1X-72 Addis) Variola virus strain Germany 1958 Orthopoxvirus 2233 Complement binding (secreted) 604 VARV-DEU58-015 60292 109724869 secreted protein Heidelberg Variola virus strain Germany 1958 Orthopoxvirus 2233 Complement control/CD46/EEV 591 VARV-DEU58-177 60454 109725031 glycoprotein Heidelberg Variola virus strain Guinea 1969 (005) Orthopoxvirus 2234 Complement binding (secreted) 604 VARV-GIN69-017 60495 94485676 secreted protein Variola virus strain Guinea 1969 (005) Orthopoxvirus 2234 Complement control/CD46/EEV 591 VARV-GIN69-181 60659 94485839 glycoprotein Variola virus strain India 1953 (Kali-Muthu- Orthopoxvirus 2238 Complement binding (secreted) 604 VARV-IND53_mad-015 61305 94485878 secreted protein M50 Madras) Variola virus strain India 1953 (Kali-Muthu- Orthopoxvirus 2238 Complement control/CD46/EEV 591 VARV-IND53_mad-179 61469 94486042 glycoprotein M50 Madras) Variola virus strain India 1953 (New Delhi) Orthopoxvirus 2239 Complement binding (secreted) 604 VARV-IND53_ndel-014 61505 94486079 secreted protein Variola virus strain India 1953 (New Delhi) Orthopoxvirus 2239 Complement control/CD46/EEV 591 VARV-IND53_ndel-178 61669 94486243 glycoprotein Variola virus strain India 1964 7124 Orthopoxvirus 2240 Complement binding (secreted) 604 VARV-IND64_vel4-016 61709 109725072 secreted protein Vellore Variola virus strain India 1964 7124 Orthopoxvirus 2240 Complement control/CD46/EEV 591 VARV-IND64_vel4-180 61873 109725236 glycoprotein Vellore Variola virus strain India 1964 7125 Orthopoxvirus 2241 Complement binding (secreted) 604 VARV-IND64_vel5-015 61913 109725277 secreted protein Vellore Variola virus strain India 1964 7125 Orthopoxvirus 2241 Complement control/CD46/EEV 591 VARV-IND64_vel5-179 62077 109725441 EEV membrane Vellore glycoprotein Variola virus strain India 3 Major 1967 Orthopoxvirus 1483 Complement binding (secreted) 604 VARV-IND3_1967-012 39174 9627533 D12L Variola virus strain India 3 Major 1967 Orthopoxvirus 1483 Complement control/CD46/EEV 591 VARV-IND3_1967-178 39340 9627696 B7R Variola virus strain Iran 1972 2602 Tabriz Orthopoxvirus 2235 Complement binding (secreted) 604 VARV-IRN72-015 60700 109725480 secreted protein Variola virus strain Iran 1972 2602 Tabriz Orthopoxvirus 2235 Complement control/CD46/EEV 591 VARV-IRN72-178 60863 109725643 glycoprotein Variola virus strain Japan 1946 (Yamada Orthopoxvirus 2243 Complement binding (secreted) 604 VARV-JPN46_yam-014 62289 94486282 secreted protein MS-2(A) Tokyo) Variola virus strain Japan 1946 (Yamada Orthopoxvirus 2243 Complement control/CD46/EEV 591 VARV-JPN46_yam-178 62453 94486446 glycoprotein MS-2(A) Tokyo) Variola virus strain Japan 1951 (Harper, Orthopoxvirus 2244 Complement binding (secreted) 604 VARV-JPN51_hrpr-014 62491 94486485 secreted protein Masterseed) Variola virus strain Japan 1951 (Harper, Orthopoxvirus 2244 Complement control/CD46/EEV 591 VARV-JPN51_hrpr-178 62655 94486649 glycoprotein Masterseed) Variola virus strain Japan 1951 (Stillwell, Orthopoxvirus 2245 Complement binding (secreted) 604 VARV-JPN51_stwl-014 62692 94486687 secreted protein Masterseed) Variola virus strain Japan 1951 (Stillwell, Orthopoxvirus 2245 Complement control/CD46/EEV 591 VARV-JPN51 stwl-178 62856 94486851 glycoprotein Masterseed) Variola virus strain Korea 1947 (Lee, Orthopoxvirus 2236 Complement binding (secreted) 604 VARV-KOR47-015 60903 94486890 secreted protein Masterseed) Variola virus strain Korea 1947 (Lee, Orthopoxvirus 2236 Complement control/CD46/EEV 591 VARV-KOR47-179 61067 94487054 glycoprotein Masterseed) Variola virus strain Kuwait 1967 (K1629) Orthopoxvirus 2237 Complement binding (secreted) 604 VARV-KWT67-015 61105 94487093 secreted protein Variola virus strain Kuwait 1967 (K1629) Orthopoxvirus 2237 Complement control/CD46/EEV 591 VARV-KWT67-178 61268 94487256 glycoprotein Variola virus strain Nepal 1973 V73-175 Orthopoxvirus 2221 Complement binding (secreted) 604 VARV-NPL73-015 57805 109725684 secreted protein Variola virus strain Nepal 1973 V73-175 Orthopoxvirus 2221 Complement control/CD46/EEV 591 VARV-NPL73-177 57967 109725846 glycoprotein Variola virus strain Niger 1969 (001, Orthopoxvirus 2222 Complement binding (secreted) 604 VARV-NER69-017 58010 94487295 secreted protein importation from Nigeria) Variola virus strain Niger 1969 (001, Orthopoxvirus 2222 Complement control/CD46/EEV 591 VARV-NER69-183 58176 94487460 glycoprotein importation from Nigeria) Variola virus strain Sierra Leone 1969 Orthopoxvirus 2223 Complement binding (secreted) 604 VARV-SLE68-017 58219 94487904 secreted protein (V68-258) Variola virus strain Sierra Leone 1969 Orthopoxvirus 2223 Complement control/CD46/EEV 591 VARV-SLE68-182 58384 94488068 glycoprotein (V68-258) Variola virus strain Somalia 1977 (V77- Orthopoxvirus 2218 Complement binding (secreted) 604 VARV-SOM77_1252-015 57203 94488107 secreted protein 1252) Variola virus strain Somalia 1977 (V77- Orthopoxvirus 2218 Complement control/CD46/EEV 591 VARV-SOM77_1252-178 57366 94488270 glycoprotein 1252) Variola virus strain Somalia 1977 (V77- Orthopoxvirus 2219 Complement binding (secreted) 604 VARV-SOM77_1605-015 57403 94488307 secreted protein 1605) Variola virus strain Somalia 1977 (V77- Orthopoxvirus 2219 Complement control/CD46/EEV 591 VARV-SOM77_1605-178 57566 94488470 glycoprotein 1605) Variola virus strain Somalia 1977 V77- Orthopoxvirus 2220 Complement binding (secreted) 604 VARV-SOM77_ali-015 57603 109726091 secreted protein 2479 Variola virus strain Somalia 1977 V77- Orthopoxvirus 2220 Complement control/CD46/EEV 591 VARV-SOM77_ali-178 57766 109726254 glycoprotein 2479 Variola virus strain South Africa 1965 (102 Orthopoxvirus 2210 Complement binding (secreted) 604 VARV-ZAF65_102-015 55587 94487499 secreted protein Natal, Ingwavuma) Variola virus strain South Africa 1965 (102 Orthopoxvirus 2210 Complement control/CD46/EEV 591 VARV-ZAF65_102-178 55750 94487662 glycoprotein Natal, Ingwavuma) Variola virus strain South Africa 1965 (103 Orthopoxvirus 2211 Complement binding (secreted) 604 VARV-ZAF65_103-015 55788 94487700 secreted protein Tvaal, Nelspruit) Variola virus strain South Africa 1965 (103 Orthopoxvirus 2211 Complement control/CD46/EEV 591 VARV-ZAF65_103-178 55951 94487863 glycoprotein Tvaal, Nelspruit) Variola virus strain Sudan 1947 (Juba) Orthopoxvirus 2212 Complement binding (secreted) 604 VARV-SDN47_jub-015 55989 94488507 secreted protein Variola virus strain Sudan 1947 (Juba) Orthopoxvirus 2212 Complement control/CD46/EEV 591 VARV-SDN47_jub-178 56152 94488670 EEV membrane glycoprotein Variola virus strain Sudan 1947 (Rumbec) Orthopoxvirus 2213 Complement binding (secreted) 604 VARV-SDN47_rum-015 56189 94488708 secreted protein Variola virus strain Sudan 1947 (Rumbec) Orthopoxvirus 2213 Complement control/CD46/EEV 591 VARV-SDN47_rum-178 56352 94488871 glycoprotein Variola virus strain Sumatra 1970 V70- Orthopoxvirus 2208 Complement binding (secreted) 604 VARV-SUM70_222-015 55185 109726294 secreted protein 222 Variola virus strain Sumatra 1970 V70- Orthopoxvirus 2208 Complement control/CD46/EEV 591 VARV-SUM70_222-177 55347 109726456 glycoprotein 222 Variola virus strain Sumatra 1970 V70- Orthopoxvirus 2209 Complement binding (secreted) 604 VARV-SUM70_228-015 55387 94488909 secreted protein 228 Variola virus strain Sumatra 1970 V70- Orthopoxvirus 2209 Complement control/CD46/EEV 591 VARV-SUM70_228-177 55549 94489071 glycoprotein 228 Variola virus strain Syria 1972 V72-199 Orthopoxvirus 2206 Complement binding (secreted) 604 VARV-SYR72-015 54781 109726497 secreted protein Variola virus strain Syria 1972 V72-199 Orthopoxvirus 2206 Complement control/CD46/EEV 591 VARV-SYR72-178 54944 109726660 glycoprotein Variola virus strain Tanzania 1965 Orthopoxvirus 2207 Complement binding (secreted) 604 VARV-TZA65-015 54984 94489109 secreted protein kembula Variola virus strain Tanzania 1965 Orthopoxvirus 2207 Complement control/CD46/EEV 591 VARV-TZA65-178 55147 94489271 glycoprotein kembula Variola virus strain United Kingdom 1946 Orthopoxvirus 2204 Complement binding (secreted) 604 VARV-GBR44_harv-015 54380 94489308 secreted protein Harvey Variola virus strain United Kingdom 1946 Orthopoxvirus 2204 Complement control/CD46/EEV 591 VARV-GBR44_harv-179 54544 94489472 glycoprotein Harvey Variola virus strain United Kingdom 1946 Orthopoxvirus 2205 Complement binding (secreted) 604 VARV-GBR46_hind-015 54582 94489511 secreted protein Hinden (Middlesex) Variola virus strain United Kingdom 1946 Orthopoxvirus 2205 Complement control/CD46/EEV 591 VARV-GBR46_hind-178 54745 94489674 glycoprotein Hinden (Middlesex) Variola virus strain United Kingdom 1947 Orthopoxvirus 2202 Complement binding (secreted) 604 VARV-GBR47_hig-015 53974 94489710 secreted protein Higgins (Staffordshire) Variola virus strain United Kingdom 1947 Orthopoxvirus 2202 Complement control/CD46/EEV 591 VARV-GBR47_hig-178 54137 94489873 glycoprotein Higgins (Staffordshire) Variola virus strain United Kingdom 1952 Orthopoxvirus 2200 Complement binding (secreted) 604 VARV-GBR52_but-019 53767 94489915 secreted protein Butler Variola virus strain United Kingdom 1952 Orthopoxvirus 2200 Complement control/CD46/EEV 591 VARV-GBR52_but-185 53933 94490080 glycoprotein Butler Variola virus strain Yugoslavia 1972 V72- Orthopoxvirus 2196 Complement binding (secreted) 604 VARV-YUG72-015 53158 94490119 secreted protein 164 Variola virus strain Yugoslavia 1972 V72- Orthopoxvirus 2196 Complement control/CD46/EEV 591 VARV-YUG72-178 53321 94490282 glycoprotein 164 Yaba monkey tumor virus strain Amano Yatapoxvirus 1503 Complement control/CD46/EEV 591 YMTV-Amano-133 43182 38229302 144R Yaba-like Disease Virus strain Davis Yatapoxvirus 1487 Complement control/CD46/EEV 591 YLDV-Davis-147 40196 12085127 144R

TABLE 5 Viral Orthologous Clusters V2.0 (VOCs) IL-1beta Gene Results Table Genome name Genus Genome id Ortholog Group Name Ortholog Group ID Gene number Gene id Genbank id Genbank name Camelpox virus strain CMS Orthopoxvirus 1493 IL-1 beta 648 CMLV-CMS-243 41339 19718172 190.5aR receptor Camelpox virus strain CMS Orthopoxvirus 1493 IL-1 beta 648 CMLV-CMS-244 41340 19718171 190R receptor Camelpox virus strain CMS Orthopoxvirus 1493 IL-1 beta 648 CMLV-CMS-246 41342 19718174 191R receptor Camelpox virus strain M96 Orthopoxvirus 1491 IL-1 beta 648 CMLV-M96-195 40901 18640427 193 receptor Camelpox virus strain M96 Orthopoxvirus 1491 IL-1 beta 648 CMLV-M96-196 40902 18640428 194 receptor Camelpox virus strain M96 Orthopoxvirus 1491 IL-1 beta 648 CMLV-M96-198 40904 18640430 196 receptor Cowpox virus strain Brighton Red Orthopoxvirus 1496 IL-1 beta 648 CPXV-BR-215 41914 20178569 209 receptor Cowpox virus strain GRI-90 Orthopoxvirus 1501 IL-1 beta 648 CPXV-GRI-197 42854 30519565 B14R receptor Cowpox virus strain Germany 91-3 Orthopoxvirus 2214 IL-1 beta 648 CPXV-GER91-197 56572 90660430 IL-1-beta- receptor inhibitor Ectromelia virus strain Moscow Orthopoxvirus 1492 IL-1 beta 648 ECTV-Mos-168 41087 22164598 163 receptor Ectromelia virus strain Naval Orthopoxvirus 1499 IL-1 beta 648 ECTV-Nav-173 42428 0 191 receptor Horsepox virus strain MNR-76 Orthopoxvirus 2230 IL-1 beta 648 HSPV-MNR76-218 59855 111184385 HSPV192 receptor Monkeypox virus strain Congo_2003_358 Orthopoxvirus 1524 IL-1 beta 648 MPXV-COG_2003_358-182 47241 68449058 189 receptor Monkeypox virus strain Liberia_1970_184 Orthopoxvirus 1525 IL-1 beta 648 MPXV-LBR_1970_184-182 47441 68449462 189 receptor Monkeypox virus strain Liberia_1970_184 Orthopoxvirus 1525 IL-1 beta 648 MPXV-LBR_1970_184-183 47442 68449463 189.5 receptor Monkeypox virus strain USA_2003_039 Orthopoxvirus 1526 IL-1 beta 648 MPXV-USA_2003_039-182 47639 68449661 189 receptor Monkeypox virus strain USA_2003_039 Orthopoxvirus 1526 IL-1 beta 648 MPXV-USA_2003_039-183 47640 68449662 189.5 receptor Monkeypox virus strain USA_2003_044 Orthopoxvirus 1522 IL-1 beta 648 MPXV-USA_2003_044-182 46841 68448859 189 receptor Monkeypox virus strain USA_2003_044 Orthopoxvirus 1522 IL-1 beta 648 MPXV-USA_2003_044-183 46842 68448860 189.5 receptor Monkeypox virus strain Zaire Orthopoxvirus 1489 IL-1 beta 648 MPXV-ZAR-178 40539 17975088 B14R receptor Monkeypox virus strain Zaire_1979-005 Orthopoxvirus 1523 IL-1 beta 648 MPXV-ZAR_1979_005-183 47040 68449260 189 receptor Monkeypox virus strain Zaire_1979-005 Orthopoxvirus 1523 IL-1 beta 648 MPXV-ZAR_1979_005-184 47041 68449261 189.5 receptor Taterapox virus strain Dahomey 1968 Orthopoxvirus 2195 IL-1 beta 648 TATV-DAH68-203 53121 113195380 IL-1-beta- receptor inhibitor Vaccinia virus strain 3737 Orthopoxvirus 1528 IL-1 beta 648 VACV-3737-199 47987 88900813 185 receptor Vaccinia virus strain Acambis 2000 Orthopoxvirus 2161 IL-1 beta 648 VACV-Acam2000-207 51263 38349065 209 receptor Vaccinia virus strain Acambis 3 Orthopoxvirus 2162 IL-1 beta 648 VACV-Acam3-209 51500 37551643 209 receptor Vaccinia virus strain Acambis 3000 Modified Orthopoxvirus 1510 IL-1 beta 648 VACV-Acam3000-186 44500 47088510 184 Virus Ankara receptor Vaccinia virus strain Copenhagen Orthopoxvirus 1485 IL-1 beta 648 VACV-Cop-250 39775 335562 B16R receptor Vaccinia virus strain Copenhagen Orthopoxvirus 1485 IL-1 beta 648 VACV-Cop-272 62885 0 receptor Vaccinia virus strain DUKE Orthopoxvirus 2458 IL-1 beta 648 VACV-DUKE-207 63587 90819859 207 receptor Vaccinia virus strain LC16m8 Orthopoxvirus 1517 IL-1 beta 648 VACV-LC16m8-265 45718 56713604 m8255R receptor Vaccinia virus strain LC16mO Orthopoxvirus 1518 IL-1 beta 648 VACV-LC16mO-265 46002 56713888 mO255R receptor Vaccinia virus strain Lister Orthopoxvirus 1519 IL-1 beta 648 VACV-Lister-265 46286 0 m8255R receptor Vaccinia virus strain Lister_VACV107 Orthopoxvirus 2659 IL-1 beta 648 VACV-Lister_VACV107-196 64529 88854278 List192 receptor Vaccinia virus strain MVA-I721 Orthopoxvirus 2696 IL-1 beta 648 VACV-MVA_I721-073 65287 0 184 receptor Vaccinia virus strain Western Reserve Orthopoxvirus 1500 IL-1 beta 648 VACV-WR-197 42636 66275994 197 receptor Vaccinia virus strain modified vaccinia Ankara Orthopoxvirus 1484 IL-1 beta 648 VACV-MVA-159 65571 2772816 MVA184R receptor Variola minor virus strain Garcia 1966 Orthopoxvirus 1482 IL-1 beta 648 VARV-Gar_1966-194 39147 5830746 D4R receptor Variola minor virus strain Garcia 1966 Orthopoxvirus 1482 IL-1 beta 648 VARV-Gar_1966-196 39149 5830748 D6R receptor Variola virus strain Afghanistan 1970 Variolator 4 Orthopoxvirus 2197 IL-1 beta 648 VARV-AFG70-187 53531 109724226 IL-1-beta- receptor inhibitor Variola virus strain Afghanistan 1970 Variolator 4 Orthopoxvirus 2197 IL-1 beta 648 VARV-AFG70-189 53533 109724228 IL-1-beta- receptor inhibitor Variola virus strain Afghanistan 1970 Variolator 4 Orthopoxvirus 2197 IL-1 beta 648 VARV-AFG70-190 53534 109724229 IL-1-beta- receptor inhibitor Variola virus strain Bangladesh 1974 Orthopoxvirus 2216 IL-1 beta 648 VARV-BGD74_shz-186 56978 94484843 IL-1-beta- (Shahzaman) receptor inhibitor Variola virus strain Bangladesh 1974 (Solaiman) Orthopoxvirus 2217 IL-1 beta 648 VARV-BGD74_sol-186 57176 94485041 IL-1-beta- receptor inhibitor Variola virus strain Bangladesh 1974 (nur islam) Orthopoxvirus 2215 IL-1 beta 648 VARV-BGD74_nur-186 56780 94484645 IL-1-beta- receptor inhibitor Variola virus strain Bangladesh 1975 v75-550 Orthopoxvirus 2198 IL-1 beta 648 VARV-BGD75_Banu-186 53733 109724429 IL-1-beta- Banu receptor inhibitor Variola virus strain Bangladesh 1975 v75-550 Orthopoxvirus 2198 IL-1 beta 648 VARV-BGD75_Banu-188 53735 109724431 IL-1-beta- Banu receptor inhibitor Variola virus strain Bangladesh 1975 v75-550 Orthopoxvirus 2198 IL-1 beta 648 VARV-BGD75_Banu-189 53736 109724432 IL-1-beta- Banu receptor inhibitor Variola virus strain Benin, Dahomey 1968 (v68- Orthopoxvirus 2224 IL-1 beta 648 VARV-BEN68-194 58604 94483831 IL-1-beta- 59) receptor inhibitor Variola virus strain Benin, Dahomey 1968 (v68- Orthopoxvirus 2224 IL-1 beta 648 VARV-BEN68-195 58605 94483832 IL-1-beta- 59) receptor inhibitor Variola virus strain Botswana 1972 (v72-143) Orthopoxvirus 2225 IL-1 beta 648 VARV-BWA72-187 58806 94484034 IL-1-beta- receptor inhibitor Variola virus strain Botswana 1972 (v72-143) Orthopoxvirus 2225 IL-1 beta 648 VARV-BWA72-188 58807 94484035 IL-1-beta- receptor inhibitor Variola virus strain Botswana 1973 (v73-225) Orthopoxvirus 2226 IL-1 beta 648 VARV-BWA73-187 59008 94484237 IL-1-beta- receptor inhibitor Variola virus strain Botswana 1973 (v73-225) Orthopoxvirus 2226 IL-1 beta 648 VARV-BWA73-188 59009 94484238 IL-1-beta- receptor inhibitor Variola virus strain Brazil 1966 (v66-39 Sao Orthopoxvirus 2227 IL-1 beta 648 VARV-BRA66-196 59219 94484444 IL-1-beta- Paulo) receptor inhibitor Variola virus strain Brazil 1966 (v66-39 Sao Orthopoxvirus 2227 IL-1 beta 648 VARV-BRA66-197 59220 94484445 IL-1-beta- Paulo) receptor inhibitor Variola virus strain China Horn 1948 Sabin Lab Orthopoxvirus 2203 IL-1 beta 648 VARV-CHN48-188 54348 109724632 IL-1-beta- July 1948 receptor inhibitor Variola virus strain China Horn 1948 Sabin Lab Orthopoxvirus 2203 IL-1 beta 648 VARV-CHN48-190 54350 109724634 IL-1-beta- July 1948 receptor inhibitor Variola virus strain China Horn 1948 Sabin Lab Orthopoxvirus 2203 IL-1 beta 648 VARV-CHN48-191 54351 109724635 IL-1-beta- July 1948 receptor inhibitor Variola virus strain Congo 1970 v70-46 Kinshasa Orthopoxvirus 2229 IL-1 beta 648 VARV-COG70_46-186 59621 109724837 IL-1-beta- receptor inhibitor Variola virus strain Congo 1970 v70-46 Kinshasa Orthopoxvirus 2229 IL-1 beta 648 VARV-COG70_46-188 59623 109724839 IL-1-beta- receptor inhibitor Variola virus strain Congo 1970 v70-46 Kinshasa Orthopoxvirus 2229 IL-1 beta 648 VARV-COG70_46-189 59624 109724840 IL-1-beta- receptor inhibitor Variola virus strain Congo 9 1970 (v74-227 Orthopoxvirus 2228 IL-1 beta 648 VARV-COG70_227-187 59421 94485240 IL-1-beta- Gispen) receptor inhibitor Variola virus strain Congo 9 1970 (v74-227 Orthopoxvirus 2228 IL-1 beta 648 VARV-COG70_227-188 59422 94485241 IL-1-beta- Gispen) receptor inhibitor Variola virus strain Ethiopia 1972 (Eth16 R14-1X- Orthopoxvirus 2231 IL-1 beta 648 VARV-ETH72_16-188 60061 94485442 IL-1-beta- 72 Addis) receptor inhibitor Variola virus strain Ethiopia 1972 (Eth16 R14-1X- Orthopoxvirus 2231 IL-1 beta 648 VARV-ETH72_16-189 60062 94485443 IL-1-beta- 72 Addis) receptor inhibitor Variola virus strain Ethiopia 1972 (Eth16 R14-1X- Orthopoxvirus 2231 IL-1 beta 648 VARV-ETH72_16-190 60063 94485444 IL-1-beta- 72 Addis) receptor inhibitor Variola virus strain Ethiopia 1972 (Eth17 R14-1X- Orthopoxvirus 2232 IL-1 beta 648 VARV-ETH72_17-188 60264 94485645 IL-1-beta- 72 Addis) receptor inhibitor Variola virus strain Germany 1958 Heidelberg Orthopoxvirus 2233 IL-1 beta 648 VARV-DEU58-186 60463 109725040 IL-1-beta- receptor inhibitor Variola virus strain Germany 1958 Heidelberg Orthopoxvirus 2233 IL-1 beta 648 VARV-DEU58-188 60465 109725042 IL-1-beta- receptor inhibitor Variola virus strain Guinea 1969 (005) Orthopoxvirus 2234 IL-1 beta 648 VARV-GIN69-192 60670 94485847 IL-1-beta- receptor inhibitor Variola virus strain Guinea 1969 (005) Orthopoxvirus 2234 IL-1 beta 648 VARV-GIN69-193 60671 94485848 IL-1-beta- receptor inhibitor Variola virus strain India 1953 (Kali-Muthu-M50 Orthopoxvirus 2238 IL-1 beta 648 VARV-IND53_mad-188 61478 94486051 IL-1-beta- Madras) receptor inhibitor Variola virus strain India 1953 (New Delhi) Orthopoxvirus 2239 IL-1 beta 648 VARV-IND53_ndel-187 61678 94486252 IL-1-beta- receptor inhibitor Variola virus strain India 1953 (New Delhi) Orthopoxvirus 2239 IL-1 beta 648 VARV-IND53_ndel-188 61679 94486253 IL-1-beta- receptor inhibitor Variola virus strain India 1964 7124 Vellore Orthopoxvirus 2240 IL-1 beta 648 VARV-IND64_vel4-189 61882 109725245 IL-1-beta- receptor inhibitor Variola virus strain India 1964 7124 Vellore Orthopoxvirus 2240 IL-1 beta 648 VARV-IND64_vel4-191 61884 109725247 IL-1-beta- receptor inhibitor Variola virus strain India 1964 7124 Vellore Orthopoxvirus 2240 IL-1 beta 648 VARV-IND64_vel4-192 61885 109725248 IL-1-beta- receptor inhibitor Variola virus strain India 1964 7125 Vellore Orthopoxvirus 2241 IL-1 beta 648 VARV-IND64_vel5-188 62086 109725450 IL-1-beta- receptor inhibitor Variola virus strain India 1964 7125 Vellore Orthopoxvirus 2241 IL-1 beta 648 VARV-IND64_vel5-190 62088 109725452 IL-1-beta- receptor inhibitor Variola virus strain India 1964 7125 Vellore Orthopoxvirus 2241 IL-1 beta 648 VARV-IND64_vel5-191 62089 109725453 IL-1-beta- receptor inhibitor Variola virus strain India 3 Major 1967 Orthopoxvirus 1483 IL-1 beta 648 VARV-IND3_1967-186 39348 9627704 B15R receptor Variola virus strain India 3 Major 1967 Orthopoxvirus 1483 IL-1 beta 648 VARV-IND3_1967-188 39350 9627706 B17R receptor Variola virus strain Iran 1972 2602 Tabriz Orthopoxvirus 2235 IL-1 beta 648 VARV-IRN72-187 60872 109725652 IL-1-beta- receptor inhibitor Variola virus strain Iran 1972 2602 Tabriz Orthopoxvirus 2235 IL-1 beta 648 VARV-IRN72-189 60874 109725654 IL-1-beta- receptor inhibitor Variola virus strain Iran 1972 2602 Tabriz Orthopoxvirus 2235 IL-1 beta 648 VARV-IRN72-190 60875 109725655 IL-1-beta- receptor inhibitor Variola virus strain Japan 1946 (Yamada MS-2(A) Orthopoxvirus 2243 IL-1 beta 648 VARV-JPN46_yam-187 62462 94486455 IL-1-beta- Tokyo) receptor inhibitor Variola virus strain Japan 1946 (Yamada MS-2(A) Orthopoxvirus 2243 IL-1 beta 648 VARV-JPN46_yam-188 62463 94486456 IL-1-beta- Tokyo) receptor inhibitor Variola virus strain Japan 1951 (Harper, Orthopoxvirus 2244 IL-1 beta 648 VARV-JPN51_hrpr-187 62664 94486658 IL-1-beta- Masterseed) receptor inhibitor Variola virus strain Japan 1951 (Stillwell, Orthopoxvirus 2245 IL-1 beta 648 VARV-JPN51_stwl-187 62865 94486860 IL-1-beta- Masterseed) receptor inhibitor Variola virus strain Japan 1951 (Stillwell, Orthopoxvirus 2245 IL-1 beta 648 VARV-JPN51_stwl-188 62866 94486861 IL-1-beta- Masterseed) receptor inhibitor Variola virus strain Korea 1947 (Lee, Orthopoxvirus 2236 IL-1 beta 648 VARV-KOR47-188 61076 94487063 IL-1-beta- Masterseed) receptor inhibitor Variola virus strain Korea 1947 (Lee, Orthopoxvirus 2236 IL-1 beta 648 VARV-KOR47-189 61077 94487064 IL-1-beta- Masterseed) receptor inhibitor Variola virus strain Kuwait 1967 (K1629) Orthopoxvirus 2237 IL-1 beta 648 VARV-KWT67-187 61277 94487265 IL-1-beta- receptor inhibitor Variola virus strain Kuwait 1967 (K1629) Orthopoxvirus 2237 IL-1 beta 648 VARV-KWT67-188 61278 94487266 IL-1-beta- receptor inhibitor Variola virus strain Nepal 1973 V73-175 Orthopoxvirus 2221 IL-1 beta 648 VARV-NPL73-186 57976 109725854 IL-1-beta- receptor inhibitor Variola virus strain Nepal 1973 V73-175 Orthopoxvirus 2221 IL-1 beta 648 VARV-NPL73-188 57978 109725856 IL-1-beta- receptor inhibitor Variola virus strain Nepal 1973 V73-175 Orthopoxvirus 2221 IL-1 beta 648 VARV-NPL73-189 57979 109725857 IL-1-beta- receptor inhibitor Variola virus strain Niger 1969 (001, importation Orthopoxvirus 2222 IL-1 beta 648 VARV-NER69-194 58187 94487468 IL-1-beta- from Nigeria) receptor inhibitor Variola virus strain Niger 1969 (001, importation Orthopoxvirus 2222 IL-1 beta 648 VARV-NER69-195 58188 94487469 IL-1-beta- from Nigeria) receptor inhibitor Variola virus strain Sierra Leone 1969 (V68-258) Orthopoxvirus 2223 IL-1 beta 648 VARV-SLE68-193 58395 94488076 IL-1-beta- receptor inhibitor Variola virus strain Sierra Leone 1969 (V68-258) Orthopoxvirus 2223 IL-1 beta 648 VARV-SLE68-194 58396 94488077 IL-1-beta- receptor inhibitor Variola virus strain Somalia 1977 (V77-1252) Orthopoxvirus 2218 IL-1 beta 648 VARV-SOM77_1252-186 57374 94488278 IL-1-beta- receptor inhibitor Variola virus strain Somalia 1977 (V77-1252) Orthopoxvirus 2218 IL-1 beta 648 VARV-SOM77_1252-187 57375 94488279 IL-1-beta- receptor inhibitor Variola virus strain Somalia 1977 (V77-1605) Orthopoxvirus 2219 IL-1 beta 648 VARV-SOM77_1605-186 57574 94488478 IL-1-beta- receptor inhibitor Variola virus strain Somalia 1977 (V77-1605) Orthopoxvirus 2219 IL-1 beta 648 VARV-SOM77_1605-187 57575 94488479 IL-1-beta- receptor inhibitor Variola virus strain Somalia 1977 V77-2479 Orthopoxvirus 2220 IL-1 beta 648 VARV-SOM77_ali-186 57774 109726262 IL-1-beta- receptor inhibitor Variola virus strain Somalia 1977 V77-2479 Orthopoxvirus 2220 IL-1 beta 648 VARV-SOM77_ali-188 57776 109726264 IL-1-beta- receptor inhibitor Variola virus strain Somalia 1977 V77-2479 Orthopoxvirus 2220 IL-1 beta 648 VARV-SOM77_ali-189 57777 109726265 IL-1-beta- receptor inhibitor Variola virus strain South Africa 1965 (102 Natal, Orthopoxvirus 2210 IL-1 beta 648 VARV-ZAF65_102-187 55759 94487671 IL-1-beta- Ingwavuma) receptor inhibitor Variola virus strain South Africa 1965 (102 Natal, Orthopoxvirus 2210 IL-1 beta 648 VARV-ZAF65_102-188 55760 94487672 IL-1-beta- Ingwavuma) receptor inhibitor Variola virus strain South Africa 1965 (103 Tvaal, Orthopoxvirus 2211 IL-1 beta 648 VARV-ZAF65_103-187 55960 94487872 IL-1-beta- Nelspruit) receptor inhibitor Variola virus strain South Africa 1965 (103 Tvaal, Orthopoxvirus 2211 IL-1 beta 648 VARV-ZAF65_103-188 55961 94487873 IL-1-beta- Nelspruit) receptor inhibitor Variola virus strain Sudan 1947 (Juba) Orthopoxvirus 2212 IL-1 beta 648 VARV-SDN47_jub-187 56161 94488679 IL-1-beta- receptor inhibitor Variola virus strain Sudan 1947 (Rumbec) Orthopoxvirus 2213 IL-1 beta 648 VARV-SDN47_rum-187 56361 94488880 IL-1-beta- receptor inhibitor Variola virus strain Sudan 1947 (Rumbec) Orthopoxvirus 2213 IL-1 beta 648 VARV-SDN47_rum-188 56362 94488881 IL-1-beta- receptor inhibitor Variola virus strain Sumatra 1970 V70-222 Orthopoxvirus 2208 IL-1 beta 648 VARV-SUM70_222-186 55356 109726465 IL-1-beta- receptor inhibitor Variola virus strain Sumatra 1970 V70-222 Orthopoxvirus 2208 IL-1 beta 648 VARV-SUM70_222-188 55358 109726467 IL-1-beta- receptor inhibitor Variola virus strain Sumatra 1970 V70-222 Orthopoxvirus 2208 IL-1 beta 648 VARV-SUM70_222-189 55359 109726468 IL-1-beta- receptor inhibitor Variola virus strain Sumatra 1970 V70-228 Orthopoxvirus 2209 IL-1 beta 648 VARV-SUM70_228-186 55558 94489080 IL-1-beta- receptor inhibitor Variola virus strain Sumatra 1970 V70-228 Orthopoxvirus 2209 IL-1 beta 648 VARV-SUM70_228-187 55559 94489081 IL-1-beta- receptor inhibitor Variola virus strain Syria 1972 V72-199 Orthopoxvirus 2206 IL-1 beta 648 VARV-SYR72-187 54953 109726669 IL-1-beta- receptor inhibitor Variola virus strain Syria 1972 V72-199 Orthopoxvirus 2206 IL-1 beta 648 VARV-SYR72-189 54955 109726671 IL-1-beta- receptor inhibitor Variola virus strain Syria 1972 V72-199 Orthopoxvirus 2206 IL-1 beta 648 VARV-SYR72-190 54956 109726672 IL-1-beta- receptor inhibitor Variola virus strain Tanzania 1965 kembula Orthopoxvirus 2207 IL-1 beta 648 VARV-TZA65-187 55156 94489278 IL-1-beta- receptor inhibitor Variola virus strain Tanzania 1965 kembula Orthopoxvirus 2207 IL-1 beta 648 VARV-TZA65-188 55157 94489279 IL-1-beta- receptor inhibitor Variola virus strain United Kingdom 1946 Harvey Orthopoxvirus 2204 IL-1 beta 648 VARV-GBR44_harv-188 54553 94489481 IL-1-beta- receptor inhibitor Variola virus strain United Kingdom 1946 Harvey Orthopoxvirus 2204 IL-1 beta 648 VARV-GBR44_harv-189 54554 94489482 IL-1-beta- receptor inhibitor Variola virus strain United Kingdom 1946 Hinden Orthopoxvirus 2205 IL-1 beta 648 VARV-GBR46_hind-187 54754 94489683 IL-1-beta- (Middlesex) receptor inhibitor Variola virus strain United Kingdom 1947 Higgins Orthopoxvirus 2202 IL-1 beta 648 VARV-GBR47_hig-187 54146 94489881 IL-1-beta- (Staffordshire) receptor inhibitor Variola virus strain United Kingdom 1947 Higgins Orthopoxvirus 2202 IL-1 beta 648 VARV-GBR47_hig-188 54147 94489882 IL-1-beta- (Staffordshire) receptor inhibitor Variola virus strain United Kingdom 1952 Butler Orthopoxvirus 2200 IL-1 beta 648 VARV-GBR52_but-196 53944 94490088 IL-1-beta- receptor inhibitor Variola virus strain United Kingdom 1952 Butler Orthopoxvirus 2200 IL-1 beta 648 VARV-GBR52_but-197 53945 94490089 IL-1-beta- receptor inhibitor Variola virus strain Yugoslavia 1972 V72-164 Orthopoxvirus 2196 IL-1 beta 648 VARV-YUG72-187 53330 94490291 IL-1-beta- receptor inhibitor Variola virus strain Yugoslavia 1972 V72-164 Orthopoxvirus 2196 IL-1 beta 648 VARV-YUG72-188 53331 94490292 IL-1-beta- receptor inhibitor

TABLE 6 Viral Orthologous Clusters V2.0 (VOCs) IL-1 receptor Gene Results Table Ortholog Ortholog Genbank Genbank Genome name Genus Genome id Group Name Group ID Gene number Gene id id name Deerpox virus strain W-1170-84 Unclassified 1516 IL-1 receptor 735 DPV-W1170_84-015 45298 0 15 (LSDV-N- 006) Deerpox virus strain W-848-83 Unclassified 1515 IL-1 receptor 735 DPV-W848_83-015 45128 62637394 15 (LSDV-N- 006) Goatpox virus strain G20-LKV Capripoxvirus 1514 IL-1 receptor 735 GTPV-G20LKV-004 44964 0 4 (LSDV-N- 006) Goatpox virus strain Pellor Capripoxvirus 1513 IL-1 receptor 735 GTPV-Pellor-004 44814 0 4 (LSDV-N- 006) Lumpy skin disease virus strain Capripoxvirus 1488 IL-1 receptor 735 LSDV-Nee-006 40209 15150445 6 Neethling 2490 (LSDV-N- 006) Lumpy skin disease virus strain Capripoxvirus 1498 IL-1 receptor 735 LSDV-LW1959-006 42100 22595698 6 Neethling vaccine LW 1959 (LSDV-N- 006) Lumpy skin disease virus strain Capripoxvirus 1497 IL-1 receptor 735 LSDV-NW_LW-006 41940 22595539 6 Neethling Warmbaths LW (LSDV-N- 006) Sheeppox virus strain A Capripoxvirus 1511 IL-1 receptor 735 SPPV-A-004 44513 0 4 (LSDV-N- 006) Sheeppox virus strain NISKHI Capripoxvirus 1512 IL-1 receptor 735 SPPV-NISKHI-003 44662 0 4 (LSDV-N- 006) Sheeppox virus strain TU-V02127 Capripoxvirus 1495 IL-1 receptor 735 SPPV-TU-004 41552 21492461 4 (LSDV-N- 006)

TABLE 7 Viral Orthologous Clusters V2.0 (VOCs) IL-18 binding protein Gene Results Table Genome Ortholog Genbank Genome name Genus id Ortholog Group Name Group ID Gene number Gene id Genbank id name Canarypox virus Avipoxvirus 1506 IL-18 BP (Avian) 312 CNPV-VR111-100 43573 40556038 100 strain ATCC VR111 Cowpox virus strain Orthopoxvirus 1496 IL-18 BP (Bsh-D7L) 599 CPXV-BR-024 41723 20178392 24 Brighton Red Cowpox virus strain Orthopoxvirus 1501 IL-18 BP (Bsh-D7L) 599 CPXV-GRI-022 42679 30519420 C8L GRI-90 Cowpox virus strain Orthopoxvirus 2214 IL-18 BP (Bsh-D7L) 599 CPXV-GER91-022 56397 90660255 interleukin- Germany 91-3 18-binding protein Deerpox virus strain Unclassified 1516 IL-18 BP (14L) 726 DPV-W1170_84- 45304 0 21 W-1170-84 021 Deerpox virus strain Unclassified 1515 IL-18 BP (14L) 726 DPV-W848_83-021 45134 62637400 21 W-848-83 Ectromelia virus Orthopoxvirus 1492 IL-18 BP (Bsh-D7L) 599 ECTV-Mos-014 40933 22164620 13 strain Moscow Ectromelia virus Orthopoxvirus 1499 IL-18 BP (Bsh-D7L) 599 ECTV-Nav-013 42268 0 19 strain Naval Fowlpox virus strain Avipoxvirus 1509 IL-18 BP (Avian) 312 FWPV-HP1_438- 44141 41023361 fp9.073 HP1-438 Munich 068 Fowlpox virus strain Avipoxvirus 1476 IL-18 BP (Avian) 312 FWPV-lowa-073 37805 9634743 73 lowa Goatpox virus strain Capripoxvirus 1514 IL-18 BP (14L) 726 GTPV-G20LKV-012 44972 0 12 G20-LKV Goatpox virus strain Capripoxvirus 1513 IL-18 BP (14L) 726 GTPV-Pellor-012 44822 0 12 Pellor Horsepox virus strain Orthopoxvirus 2230 IL-18 BP (Bsh-D7L) 599 HSPV-MNR76-027 59664 111184194 HSPV019 MNR-76 Lumpy skin disease Capripoxvirus 1488 IL-18 BP (14L) 726 LSDV-Nee-015 40218 15150454 15 virus strain Neethling 2490 Lumpy skin disease Capripoxvirus 1497 IL-18 BP (14L) 726 LSDV-NW_LW-015 41949 22595548 15 virus strain Neethling Warmbaths LW Lumpy skin disease Capripoxvirus 1498 IL-18 BP (14L) 726 LSDV-LW1959-015 42109 22595707 15 virus strain Neethling vaccine LW 1959 Molluscum Molluscipoxvirus 1477 IL-18 BP (14L) 726 MOCV-st1-055 38049 9628986 054L contagiosum virus strain subtype 1 Monkeypox Virus Orthopoxvirus 1502 IL-18 BP (Bsh-D7L) 599 MPXV-WR267-009 42880 0 9 strain Walter Reed 267 Monkeypox virus Orthopoxvirus 1520 IL-18 BP (Bsh-D7L) 599 MPXV-COP58-009 46314 59858815 9 strain COP-58 Monkeypox virus Orthopoxvirus 1524 IL-18 BP (Bsh-D7L) 599 MPXV- 47070 68448887 14 strain COG_2003_358- Congo_2003_358 011 Monkeypox virus Orthopoxvirus 1525 IL-18 BP (Bsh-D7L) 599 MPXV- strain LBR_1970_184- 47270 68449291 14 Liberia_1970_184 011 Monkeypox virus Orthopoxvirus 1521 IL-18 BP (Bsh-D7L) 599 MPXV-SLE-009 46491 58220479 9 strain Sierra Leone Monkeypox virus Orthopoxvirus 1526 IL-18 BP (Bsh-D7L) 599 MPXV- 47468 68449490 14 strain USA_2003_039- USA_2003_039 011 Monkeypox virus Orthopoxvirus 1522 IL-18 BP (Bsh-D7L) 599 MPXV- 46670 68448688 14 strain USA_2003_044- USA_2003_044 011 Monkeypox virus Orthopoxvirus 1489 IL-18 BP (Bsh-D7L) 599 MPXV-ZAR-009 40370 17974922 D6L strain Zaire Monkeypox virus Orthopoxvirus 1523 IL-18 BP (Bsh-D7L) 599 MPXV- 46868 68449088 14 strain Zaire_1979- ZAR_1979_005- 005 011 Rabbitpox virus Orthopoxvirus 1494 IL-18 BP (Bsh-D7L) 599 RPXV-Utr-009 41371 44971372 9 strain Utrecht Sheeppox virus Capripoxvirus 1511 IL-18 BP (14L) 726 SPPV-A-012 44521 0 12 strain A Sheeppox virus Capripoxvirus 1512 IL-18 BP (14L) 726 SPPV-NISKHI-011 44670 0 12 strain NISKHI Sheeppox virus Capripoxvirus 1495 IL-18 BP (14L) 726 SPPV-TU-012 41560 21492469 12 strain TU-V02127 Swinepox virus Suipoxvirus 1490 IL-18 BP (14L) 726 SWPV-Neb-011 40566 18640097 11 strain Nebraska 17077-99 Tanapox virus strain Yatapoxvirus 3496 IL-18 BP (14L) 726 TANV-KEN-015 67471 146746350 14L Kenya Tanapox virus strain Yatapoxvirus 3497 IL-18 BP (14L) 726 TANV-COD-014 67561 146746506 14L isolate TPV-RoC Taterapox virus Orthopoxvirus 2195 IL-18 BP (Bsh-D7L) 599 TATV-DAH68-017 52935 113195194 interleukin- strain Dahomey 18-binding 1968 protein Vaccinia virus strain Orthopoxvirus 1528 IL-18 BP (Bsh-D7L) 599 VACV-3737-016 47804 88900632 11 3737 Vaccinia virus strain Orthopoxvirus 1528 IL-18 BP (Bsh-D7L) 599 VACV-3737-207 47995 88900821 12 3737 Vaccinia virus strain Orthopoxvirus 2161 IL-18 BP (Bsh-D7L) 599 VACV-Acam2000- 51075 38348877 19 Acambis 2000 019 Vaccinia virus strain Orthopoxvirus 2161 IL-18 BP (Bsh-D7L) 599 VACV-Acam2000- 51274 38349076 224 Acambis 2000 218 Vaccinia virus strain Orthopoxvirus 2162 IL-18 BP (Bsh-D7L) 599 VACV-Acam3-019 51310 37551453 19 Acambis 3 Vaccinia virus strain Orthopoxvirus 1510 IL-18 BP (Bsh-D7L) 599 VACV-Acam3000- 44324 47088336 10 Acambis 3000 010 Modified Virus Ankara Vaccinia virus strain Orthopoxvirus 2458 IL-18 BP (Bsh-D7L) 599 VACV-DUKE-019 63399 90819671 19 DUKE Vaccinia virus strain Orthopoxvirus 1517 IL-18 BP (Bsh-D7L) 599 VACV-LC16m8-021 45474 56713362 m8009L LC16m8 Vaccinia virus strain Orthopoxvirus 1518 IL-18 BP (Bsh-D7L) 599 VACV-LC16mO- 45758 56713646 mO009L LC16mO 021 Vaccinia virus strain Orthopoxvirus 1519 IL-18 BP (Bsh-D7L) 599 VACV-Lister-021 46042 0 m8009L Lister Vaccinia virus strain Orthopoxvirus 2659 IL-18 BP (Bsh-D7L) 599 VACV- 64350 88854042 List013 Lister_VACV107 Lister_VACV107- 017 Vaccinia virus strain Orthopoxvirus 2696 IL-18 BP (Bsh-D7L) 599 VACV-MVA_I721- 65312 0 10 MVA-I721 098 Vaccinia virus strain Orthopoxvirus 1500 IL-18 BP (Bsh-D7L) 599 VACV-WR-013 42450 66275810 13 Western Reserve Vaccinia virus strain Orthopoxvirus 1484 IL-18 BP (Bsh-D7L) 599 VACV-MVA-004 65422 2772664 MVA008L modified vaccinia Ankara Variola major virus Orthopoxvirus 1481 IL-18 BP (Bsh-D7L) 599 VARV-BGD75maj- 38768 438922 D7L strain Bangladesh 007 1975 Variola minor virus Orthopoxvirus 1482 IL-18 BP (Bsh-D7L) 599 VARV-Gar_1966- 38959 5830561 B6L strain Garcia 1966 006 Variola virus strain Orthopoxvirus 2197 IL-18 BP (Bsh-D7L) 599 VARV-AFG70-006 53350 109724045 interleukin- Afghanistan 1970 18-binding Variolator 4 protein Variola virus strain Orthopoxvirus 2216 IL-18 BP (Bsh-D7L) 599 VARV-BGD74_shz- 56798 94484663 interleukin- Bangladesh 1974 006 18-binding (Shahzaman) protein Variola virus strain Orthopoxvirus 2217 IL-18 BP (Bsh-D7L) 599 VARV-BGD74_sol- 56996 94484861 interleukin- Bangladesh 1974 006 18-binding (Solaiman) protein Variola virus strain Orthopoxvirus 2215 IL-18 BP (Bsh-D7L) 599 VARV-BGD74_nur- 56600 94484466 interleukin- Bangladesh 1974 006 18-binding (nur islam) protein Variola virus strain Orthopoxvirus 2198 IL-18 BP (Bsh-D7L) 599 VARV- 53553 109724249 interleukin- Bangladesh 1975 BGD75_Banu-006 18-binding v75-550 Banu protein Variola virus strain Orthopoxvirus 2224 IL-18 BP (Bsh-D7L) 599 VARV-BEN68-006 58416 94483647 interleukin- Benin, Dahomey 18-binding 1968 (v68-59) protein Variola virus strain Orthopoxvirus 2225 IL-18 BP (Bsh-D7L) 599 VARV-BWA72-006 58625 94483853 interleukin- Botswana 1972 (v72- 18-binding 143) protein Variola virus strain Orthopoxvirus 2226 IL-18 BP (Bsh-D7L) 599 VARV-BWA73-006 58827 94484056 interleukin- Botswana 1973 (v73- 18-binding 225) protein Variola virus strain Orthopoxvirus 2227 IL-18 BP (Bsh-D7L) 599 VARV-BRA66-006 59029 94484258 interleukin- Brazil 1966 (v66-39 18-binding Sao Paulo) protein Variola virus strain Orthopoxvirus 2203 IL-18 BP (Bsh-D7L) 599 VARV-CHN48-006 54166 109724451 interleukin- China Horn 1948 18-binding Sabin Lab July 1948 protein Variola virus strain Orthopoxvirus 2229 IL-18 BP (Bsh-D7L) 599 VARV-COG70_46- 59441 109724656 interleukin- Congo 1970 v70-46 006 18-binding Kinshasa protein Variola virus strain Orthopoxvirus 2228 IL-18 BP (Bsh-D7L) 599 VARV-COG70_227- 59240 94485059 interleukin- Congo 9 1970 (v74- 006 18-binding 227 Gispen) protein Variola virus strain Orthopoxvirus 2231 IL-18 BP (Bsh-D7L) 599 VARV-ETH72_16- 59879 94485260 interleukin- Ethiopia 1972 (Eth16 006 18-binding R14-1X-72 Addis) protein Variola virus strain Orthopoxvirus 2232 IL-18 BP (Bsh-D7L) 599 VARV-ETH72_17- 60082 94485463 interleukin- Ethiopia 1972 (Eth17 006 18-binding R14-1X-72 Addis) protein Variola virus strain Orthopoxvirus 2233 IL-18 BP (Bsh-D7L) 599 VARV-DEU58-006 60283 109724860 interleukin- Germany 1958 18-binding Heidelberg protein Variola virus strain Orthopoxvirus 2234 IL-18 BP (Bsh-D7L) 599 VARV-GIN69-006 60484 94485665 interleukin- Guinea 1969 (005) 18-binding protein Variola virus strain Orthopoxvirus 2238 IL-18 BP (Bsh-D7L) 599 VARV-IND53_mad- 61296 94485869 interleukin- India 1953 (Kali- 006 18-binding Muthu-M50 Madras) protein Variola virus strain Orthopoxvirus 2239 IL-18 BP (Bsh-D7L) 599 VARV-IND53_ndel- 61497 94486071 interleukin- India 1953 (New 006 18-binding Delhi) protein Variola virus strain Orthopoxvirus 2240 IL-18 BP (Bsh-D7L) 599 VARV-IND64_vel4- 61700 109725063 interleukin- India 1964 7124 007 18-binding Vellore protein Variola virus strain Orthopoxvirus 2241 IL-18 BP (Bsh-D7L) 599 VARV-IND64_vel5- 61904 109725268 interleukin- India 1964 7125 006 18-binding Vellore protein Variola virus strain Orthopoxvirus 1483 IL-18 BP (Bsh-D7L) 599 VARV-IND3_1967- 39167 9627526 D5L India 3 Major 1967 005 Variola virus strain Orthopoxvirus 2235 IL-18 BP (Bsh-D7L) 599 VARV-IRN72-006 60691 109725471 interleukin- Iran 1972 2602 18-binding Tabriz protein Variola virus strain Orthopoxvirus 2243 IL-18 BP (Bsh-D7L) 599 VARV-JPN46_yam- 62281 94486274 interleukin- Japan 1946 006 18-binding (Yamada MS-2(A) protein Tokyo) Variola virus strain Orthopoxvirus 2244 IL-18 BP (Bsh-D7L) 599 VARV-JPN51_hrpr- 62483 94486477 interleukin- Japan 1951 (Harper, 006 18-binding Masterseed) protein Variola virus strain Orthopoxvirus 2245 IL-18 BP (Bsh-D7L) 599 VARV-JPN51_stwl- 62684 94486679 interleukin- Japan 1951 006 18-binding (Stillwell, protein Masterseed) Variola virus strain Orthopoxvirus 2236 IL-18 BP (Bsh-D7L) 599 VARV-KOR47-006 60894 94486881 interleukin- Korea 1947 (Lee, 18-binding Masterseed) protein Variola virus strain Orthopoxvirus 2237 IL-18 BP (Bsh-D7L) 599 VARV-KWT67-006 61096 94487084 interleukin- Kuwait 1967 (K1629) 18-binding protein Variola virus strain Orthopoxvirus 2221 IL-18 BP (Bsh-D7L) 599 VARV-NPL73-006 57796 109725675 interleukin- Nepal 1973 V73-175 18-binding protein Variola virus strain Orthopoxvirus 2222 IL-18 BP (Bsh-D7L) 599 VARV-NER69-006 57999 94487284 interleukin- Niger 1969 (001, 18-binding importation from protein Nigeria) Variola virus strain Orthopoxvirus 2223 IL-18 BP (Bsh-D7L) 599 VARV-SLE68-006 58208 94487893 interleukin- Sierra Leone 1969 18-binding (V68-258) protein Variola virus strain Orthopoxvirus 2218 IL-18 BP (Bsh-D7L) 599 VARV- 57194 94488098 interleukin- Somalia 1977 (V77- SOM77_1252-006 18-binding 1252) protein Variola virus strain Orthopoxvirus 2219 IL-18 BP (Bsh-D7L) 599 VARV- 57394 94488298 interleukin- Somalia 1977 (V77- SOM77_1605-006 18-binding 1605) protein Variola virus strain Orthopoxvirus 2220 1L-18 BP (Bsh-D7L) 599 VARV-SOM77_ali- 57594 109726082 interleukin- Somalia 1977 V77- 006 18-binding 2479 protein Variola virus strain Orthopoxvirus 2210 IL-18 BP (Bsh-D7L) 599 VARV-ZAF65_102- 55578 94487490 interleukin- South Africa 1965 006 18-binding (102 Natal, protein Ingwavuma) Variola virus strain Orthopoxvirus 2211 IL-18 BP (Bsh-D7L) 599 VARV-ZAF65_103- 55779 94487691 interleukin- South Africa 1965 006 18-binding (103 Tvaal, protein Nelspruit) Variola virus strain Orthopoxvirus 2212 IL-18 BP (Bsh-D7L) 599 VARV-SDN47_jub- 55980 94488498 interleukin- Sudan 1947 (Juba) 006 18-binding protein Variola virus strain Orthopoxvirus 2213 IL-18 BP (Bsh-D7L) 599 VARV-SDN47_rum- 56180 94488699 interleukin- Sudan 1947 006 18-binding (Rumbec) protein Variola virus strain Orthopoxvirus 2208 IL-18 BP (Bsh-D7L) 599 VARV-SUM70_222- 55176 109726285 interleukin- Sumatra 1970 V70- 006 18-binding 222 protein Variola virus strain Orthopoxvirus 2209 IL-18 BP (Bsh-D7L) 599 VARV-SUM70_228- 55378 94488900 interleukin- Sumatra 1970 V70- 006 18-binding 228 protein Variola virus strain Orthopoxvirus 2206 IL-18 BP (Bsh-D7L) 599 VARV-SYR72-006 54772 109726488 interleukin- Syria 1972 V72-199 18-binding protein Variola virus strain Orthopoxvirus 2207 IL-18 BP (Bsh-D7L) 599 VARV-TZA65-006 54975 94489100 interleukin- Tanzania 1965 18-binding kembula protein Variola virus strain Orthopoxvirus 2204 IL-18 BP (Bsh-D7L) 599 VARV-GBR44_harv- 54371 94489299 interleukin- United Kingdom 006 18-binding 1946 Harvey protein Variola virus strain Orthopoxvirus 2205 IL-18 BP (Bsh-D7L) 599 VARV-GBR46_hind- 54573 94489502 interleukin- United Kingdom 006 18-binding 1946 Hinden protein (Middlesex) Variola virus strain Orthopoxvirus 2202 IL-18 BP (Bsh-D7L) 599 VARV-GBR47_hig- 53965 94489701 interleukin- United Kingdom 006 18-binding 1947 Higgins protein (Staffordshire) Variola virus strain Orthopoxvirus 2200 IL-18 BP (Bsh-D7L) 599 VARV-GBR52_but- 53754 94489902 interleukin- United Kingdom 006 18-binding 1952 Butler protein Variola virus strain Orthopoxvirus 2196 IL-18 BP (Bsh-D7L) 599 VARV-YUG72-006 53149 94490110 interleukin- Yugoslavia 1972 18-binding V72-164 protein Yaba monkey tumor Yatapoxvirus 1503 IL-18 BP (14L) 726 YMTV-Amano-010 43059 38229179 14L virus strain Amano Yaba-like Disease Yatapoxvirus 1487 IL-18 BP (14L) 726 YLDV-Davis-014 40063 12084997 14L Virus strain Davis

TABLE 8 Viral Orthologous Clusters V2.0 (VOCs) INF-gamma Gene Results Table Ortholog Genome Ortholog Group Gene Gen- Genome name Genus id Group Name ID Gene number id bank id Genbank name Camelpox virus Orthopoxvirus 1493 IFN-gamma 564 CMLV-CMS-233 41329 19718161 181R strain CMS receptor Camelpox virus Orthopoxvirus 1491 IFN-gamma 564 CMLV-M96-186 40892 18640418 184 strain M96 receptor Cowpox virus Orthopoxvirus 1496 IFN-gamma 564 CPXV-BR-208 41907 20178562 202 strain Brighton Red receptor Cowpox virus strain Orthopoxvirus 1501 IFN-gamma 564 CPXV-GRI-190 42847 30519558 B7R GRI-90 receptor Cowpox virus strain Orthopoxvirus 2214 IFN-gamma 564 CPXV-GER91-189 56564 90660422 interferon-gamma Germany 91-3 receptor receptor-like Deerpox virus strain Unclassified 1516 IFN-gamma 564 DPV-W1170_84-010 45293 0  10 W-1170-84 receptor Deerpox virus strain Unclassified 1515 IFN-gamma 564 DPV-W848_83-010 45123 62637389  10 W-848-83 receptor Ectromelia virus Orthopoxvirus 1492 IFN-gamma 564 ECTV-Mos-163 41082 22164593 158 strain Moscow receptor Ectromelia virus Orthopoxvirus 1499 IFN-gamma 564 ECTV-Nav-168 42423 0 185 strain Naval receptor Goatpox virus Capripoxvirus 1514 IFN-gamma 564 GTPV-G20LKV-006 44966 0  6 strain G20-LKV receptor Goatpox virus Capripoxvirus 1513 IFN-gamma 564 GTPV-Pellor-006 44816 0  6 strain Pellor receptor Horsepox virus Orthopoxvirus 2230 IFN-gamma 564 HSPV-MNR76-211 59848 111184378 HSPV185 strain MNR-76 receptor Lumpy skin disease Capripoxvirus 1488 IFN-gamma 564 LSDV-Nee-008 40211 15150447  8 virus strain receptor Neethling 2490 Lumpy skin disease Capripoxvirus 1497 IFN-gamma 564 LSDV-NW_LW-008 41942 22595541  8 virus strain receptor Neethling Warmbaths LW Lumpy skin disease Capripoxvirus 1498 IFN-gamma 564 LSDV-LW1959-008 42102 22595700  8 virus strain receptor Neethling vaccine LW 1959 Monkeypox Virus Orthopoxvirus 1502 IFN-gamma 564 MPXV-WR267-163 43034 0 162 strain Walter receptor Reed 267 Monkeypox virus Orthopoxvirus 1520 IFN-gamma 564 MPXV-COP58-162 46467 59858968 162 strain COP-58 receptor Monkeypox Orthopoxvirus 1524 IFN-gamma 564 MPXV-COG_2003_358-1 47235 68449052 183 virus strain receptor Congo_2003_358 Monkeypox Orthopoxvirus 1525 IFN-gamma 564 MPXV-LBR_1970_184-17 47434 68449455 183 virus strain receptor Liberia_1970_184 Monkeypox virus Orthopoxvirus 1521 IFN-gamma 564 MPXV-SLE-162 46644 58220632 162 strain Sierra Leone receptor Monkeypox Orthopoxvirus 1526 IFN-gamma 564 MPXV-USA_2003_039-17 47633 68449655 183 virus strain receptor USA_2003_039 Monkeypox Orthopoxvirus 1522 IFN-gamma 564 MPXV-USA_2003_044-17 46835 68448853 183 virus strain receptor USA_2003_044 Monkeypox virus Orthopoxvirus 1489 IFN-gamma 564 MPXV-ZAR-173 40534 17975083 B9R strain Zaire receptor Monkeypox Orthopoxvirus 1523 IFN-gamma 564 MPXV-ZAR_1979_005-17 47034 68449254 183 virus strain receptor Zaire_1979-005 Myxoma virus strain Leporipoxvirus 1479 IFN-gamma 564 MYXV-Lau-010 38435 9633801 m007L Lausanne receptor Myxoma virus strain Leporipoxvirus 1479 IFN-gamma 564 MYXV-Lau-162 38586 9633642 m007R Lausanne receptor Rabbit fibroma virus Leporipoxvirus 1480 IFN-gamma 564 SFV-Kas-009 38604 9633817 gp007L strain Kasza receptor Rabbit fibroma virus Leporipoxvirus 1480 IFN-gamma 564 SFV-Kas-158 38753 9633962 gp007R strain Kasza receptor Rabbitpox virus Orthopoxvirus 1494 IFN-gamma 564 RPXV-Utr-172 41534 44971533 170 strain Utrecht receptor Sheeppox virus Capripoxvirus 1511 IFN-gamma 564 SPPV-A-006 44515 0  6 strain A receptor Sheeppox virus Capripoxvirus 1512 IFN-gamma 564 SPPV-NISKHI-005 44664 0  6 strain NISKHI receptor Sheeppox virus strain Capripoxvirus 1495 IFN-gamma 564 SPPV-TU-006 41554 21492463  6 TU-V02127 receptor Swinepox virus strain Suipoxvirus 1490 IFN-gamma 564 Neb-008 40563 18640094  8 Nebraska 17077-99 receptor Taterapox virus strain Orthopoxvirus 2195 IFN-gamma 564 TATV-DAH68-191 53109 113195368 interferon-gamma Dahomey 1968 receptor receptor-like protein Vaccinia virus strain Orthopoxvirus 1528 IFN-gamma 564 VACV-3737-191 47979 88900807 180 3737 receptor Vaccinia virus strain Orthopoxvirus 2161 IFN-gamma 564 VACV-Acam2000-199 51255 38349057 201 Acambis 2000 receptor Vaccinia virus strain Orthopoxvirus 2162 IFN-gamma 564 VACV-Acam3-201 51492 37551635 201 Acambis 3 receptor Vaccinia virus strain Orthopoxvirus 1510 IFN-gamma 564 VACV-Acam3000-178 44492 47088502 176 Acambis receptor 3000 Modified Virus Ankara Vaccinia virus strain Orthopoxvirus 1485 IFN-gamma 564 VACV-Cop-241 39766 335553 B8R Copenhagen receptor Vaccinia virus Orthopoxvirus 2458 IFN-gamma 564 VACV-DUKE-199 63579 90819851 199 strain DUKE receptor Vaccinia virus Orthopoxvirus 1517 IFN-gamma 564 VACV-LC16m8-257 45710 56713596 m8247R strain LC16m8 receptor Vaccinia virus Orthopoxvirus 1518 IFN-gamma 564 VACV-LC16mO-257 45994 56713880 mO247R strain LC16mO receptor Vaccinia virus Orthopoxvirus 1519 IFN-gamma 564 VACV-Lister-257 46278 0 m8247R strain Lister receptor Vaccinia virus strain Orthopoxvirus 2659 IFN-gamma 564 VACV-Lister_VACV107-1$$ 64522 88854272 List185 Lister_VACV107 receptor Vaccinia virus Orthopoxvirus 2696 IFN-gamma 564 VACV-MVA_I721-089 65303 0 176 strain MVA-I721 receptor Vaccinia virus strain Orthopoxvirus 1500 IFN-gamma 564 VACV-WR-190 42629 66275987 190 Western Reserve receptor Variola major virus Orthopoxvirus 1481 IFN-gamma 564 VARV-BGD75maj-175 38936 439086 B8R strain Bangladesh receptor 1975 Variola minor virus Orthopoxvirus 1482 IFN-gamma 564 VARV-Gar_1966-187 39140 5830739 H9R strain Garcia 1966 receptor Variola virus Orthopoxvirus 2197 IFN-gamma 564 VARV-AFG70-181 53525 109724220 interferon-gamma strain Afghanistan receptor receptor-like 1970 Variolator 4 soluble protein Variola virus strain Orthopoxvirus 2216 IFN-gamma 564 VARV-BGD74_shz-180 56972 94484837 interferon-gamma Bangladesh receptor receptor-like 1974 (Shahzaman) soluble protein Variola virus strain Orthopoxvirus 2217 IFN-gamma 564 VARV-BGD74_sol-180 57170 94485035 interferon-gamma Bangladesh receptor receptor-like 1974 (Solaiman) soluble protein Variola virus strain Orthopoxvirus 2215 IFN-gamma 564 VARV-BGD74_nur-180 56774 94484639 interferon-gamma Bangladesh receptor receptor-like 1974 (nur islam) soluble protein Variola virus strain Orthopoxvirus 2198 IFN-gamma 564 VARV-BGD75_Banu-180 53727 109724423 interferon-gamma Bangladesh receptor receptor-like 1975 v75-550 Banu soluble protein Variola virus Orthopoxvirus 2224 IFN-gamma 564 VARV-BEN68-185 58595 94483824 interferon-gamma strain Benin, receptor receptor-like Dahomey 1968 soluble protein (v68-59) Variola virus strain Orthopoxvirus 2225 IFN-gamma 564 VARV-BWA72-181 58800 94484028 interferon-gamma Botswana receptor receptor-like 1972 (v72-143) soluble protein Variola virus Orthopoxvirus 2226 IFN-gamma 564 VARV-BWA73-181 59002 94484231 interferon-gamma strain Botswana receptor receptor-like 1973 (v73-225) soluble protein Variola virus strain Orthopoxvirus 2227 IFN-gamma 564 VARV-BRA66-188 59211 94484438 interferon-gamma Brazil 1966 receptor receptor-like (v66-39 Sao Paulo) soluble protein Variola virus strain Orthopoxvirus 2203 IFN-gamma 564 VARV-CHN48-182 54342 109724626 interferon-gamma China Horn receptor receptor-like 1948 Sabin Lab soluble protein July 1948 Variola virus strain Orthopoxvirus 2229 IFN-gamma 564 VARV-COG70_46-180 59615 109724831 interferon-gamma Congo 1970 receptor receptor-like v70-46 Kinshasa soluble protein Variola virus strain Orthopoxvirus 2228 IFN-gamma 564 VARV-COG70_227-181 59415 94485234 interferon-gamma Congo 9 receptor receptor-like 1970 (v74-227 Gispen) soluble protein Variola virus strain Orthopoxvirus 2231 IFN-gamma 564 VARV-ETH72_16-182 60055 94485436 interferon-gamma Ethiopia receptor receptor-like 1972 (Eth16 R14-1X- soluble protein 72 Addis) Variola virus strain Orthopoxvirus 2232 IFN-gamma 564 VARV-ETH72_17-182 60258 94485639 interferon-gamma Ethiopia receptor receptor-like 1972 (Eth17 R14-1X- soluble protein 72 Addis) Variola virus strain Orthopoxvirus 2233 IFN-gamma 564 VARV-DEU58-180 60457 109725034 interferon-gamma Germany receptor receptor-like 1958 Heidelberg soluble protein Variola virus Orthopoxvirus 2234 IFN-gamma 564 VARV-GIN69-184 60662 94485841 interferon-gamma strain Guinea receptor receptor-like 1969 (005) soluble protein Variola virus strain Orthopoxvirus 2238 IFN-gamma 564 VARV-IND53_mad-182 61472 94486045 interferon-gamma India 1953 receptor receptor-like (Kali-Muthu-M50 soluble protein Madras) Variola virus strain Orthopoxvirus 2239 IFN-gamma 564 VARV-IND53_ndel-181 61672 94486246 interferon-gamma India 1953 receptor receptor-like (New Delhi) soluble protein Variola virus strain Orthopoxvirus 2240 IFN-gamma 564 VARV-IND64_vel4-183 61876 109725239 interferon-gamma India 1964 receptor receptor-like 7124 Vellore soluble protein Variola virus strain Orthopoxvirus 2241 IFN-gamma 564 VARV-IND64_vel5-182 62080 109725444 interferon-gamma India 1964 receptor receptor-like protein 7125 Vellore Variola virus strain Orthopoxvirus 1483 IFN-gamma 564 VARV-IND3_1967-180 39342 9627698 B9R India 3 Major 1967 receptor Variola virus strain Orthopoxvirus 2235 IFN-gamma 564 VARV-IRN72-181 60866 109725646 interferon-gamma Iran 1972 receptor receptor-like 2602 Tabriz soluble protein Variola virus strain Orthopoxvirus 2243 IFN-gamma 564 VARV-JPN46_yam-181 62456 94486449 interferon-gamma Japan 1946 receptor receptor-like (Yamada MS-2(A) soluble protein Tokyo) Variola virus strain Orthopoxvirus 2244 IFN-gamma 564 VARV-JPN51_hrpr-181 62658 94486652 interferon-gamma Japan 1951 receptor receptor-like (Harper, Masterseed) soluble protein Variola virus strain Orthopoxvirus 2245 IFN-gamma 564 VARV-JPN51_stwl-181 62859 94486854 interferon-gamma Japan 1951 receptor receptor-like (Stillwell, Masterseed) soluble protein Variola virus strain Orthopoxvirus 2236 IFN-gamma 564 VARV-KOR47-182 61070 94487057 interferon-gamma Korea 1947 receptor receptor-like (Lee, Masterseed) soluble protein Variola virus strain Orthopoxvirus 2237 IFN-gamma 564 VARV-KWT67-181 61271 94487259 interferon-gamma Kuwait 1967 receptor receptor-like (K1629) soluble protein Variola virus strain Orthopoxvirus 2221 IFN-gamma 564 VARV-NPL73-180 57970 109725849 interferon-gamma Nepal 1973 receptor receptor-like V73-175 soluble protein Variola virus strain Orthopoxvirus 2222 IFN-gamma 564 VARV-NER69-186 58179 94487462 interferon-gamma Niger 1969 receptor receptor-like (001, importation soluble protein from Nigeria) Variola virus Orthopoxvirus 2223 IFN-gamma 564 VARV-SLE68-185 58387 94488070 interferon-gamma strain Sierra receptor receptor-like Leone 1969 (V68-258) soluble protein Variola virus Orthopoxvirus 2218 IFN-gamma 564 VARV-SOM77_1252-180 57368 94488272 interferon-gamma strain Somalia receptor receptor-like 1977 (V77-1252) soluble protein Variola virus Orthopoxvirus 2219 IFN-gamma 564 VARV-SOM77_1605-180 57568 94488472 interferon-gamma strain Somalia receptor receptor-like 1977 (V77-1605) soluble protein Variola virus Orthopoxvirus 2220 IFN-gamma 564 VARV-SOM77_ali-180 57768 109726256 interferon-gamma strain Somalia receptor receptor-like 1977 V77-2479 soluble protein Variola virus strain Orthopoxvirus 2210 IFN-gamma 564 VARV-ZAF65_102-181 55753 94487665 interferon-gamma South Africa receptor receptor-like 1965 (102 Natal, soluble protein Ingwavuma) Variola virus strain Orthopoxvirus 2211 IFN-gamma 564 VARV-ZAF65_103-181 55954 94487866 interferon-gamma South Africa receptor receptor-like 1965 (103 Tvaal, soluble protein Nelspruit) Variola virus strain Orthopoxvirus 2212 IFN-gamma 564 VARV-SDN47_jub-181 56155 94488673 interferon-gamma Sudan 1947 receptor receptor-like (Juba) soluble protein Variola virus strain Orthopoxvirus 2213 IFN-gamma 564 VARV-SDN47_rum-181 56355 94488874 interferon-gamma Sudan 1947 receptor receptor-like (Rumbec) soluble protein Variola virus Orthopoxvirus 2208 IFN-gamma 564 VARV-SUM70_222-180 55350 109726459 interferon-gamma strain Sumatra receptor receptor-like 1970 V70-222 soluble protein Variola virus Orthopoxvirus 2209 IFN-gamma 564 VARV-SUM70_228-180 55552 94489074 interferon-gamma strain Sumatra receptor receptor-like 1970 V70-228 soluble protein Variola virus Orthopoxvirus 2206 IFN-gamma 564 VARV-SYR72-181 54947 109726663 interferon-gamma strain Syria 1972 receptor receptor-like V72-199 soluble protein Variola virus Orthopoxvirus 2207 IFN-gamma 564 VARV-TZA65-181 55150 94489273 interferon-gamma strain Tanzania receptor receptor-like 1965 kembula soluble protein Variola virus Orthopoxvirus 2204 IFN-gamma 564 VARV-GBR44_harv-182 54547 94489475 interferon-gamma strain United receptor receptor-like Kingdom 1946 Harvey soluble protein Variola virus Orthopoxvirus 2205 IFN-gamma 564 VARV-GBR46_hind-181 54748 94489677 interferon-gamma strain United receptor receptor-like Kingdom 1946 Hinden soluble protein (Middlesex) Variola virus Orthopoxvirus 2202 IFN-gamma 564 VARV-GBR47_hig-181 54140 94489875 interferon-gamma strain United receptor receptor-like Kingdom 1947 soluble protein Higgins (Staffordshire) Variola virus Orthopoxvirus 2200 IFN-gamma 564 VARV-GBR52_but-188 53936 94490082 interferon-gamma strain United receptor receptor-like Kingdom 1952 Butler soluble protein Variola virus Orthopoxvirus 2196 IFN-gamma 564 VARV-YUG72-181 53324 94490285 interferon-gamma strain Yugoslavia receptor receptor-like 1972 V72-164 soluble protein

TABLE 9 Viral Orthologous Clusters V2.0 (VOCs) Interferonalpha-beta Gene Results Table Genome Ortholog Ortholog Gene Genbank Genome name Genus id Group Name Group ID Gene number Id id Genbank name Camelpox virus strain CMS Orthopoxvirus 1493 IFN-alpha/beta 584 CMLV-CMS-252 41348 19718180 196R receptor Camelpox virus strain M96 Orthopoxvirus 1491 IFN-alpha/beta 584 CMLV-M96-203 40909 18640435 201 receptor Cowpox virus strain Brighton Orthopoxvirus 1496 IFN-alpha/beta 584 CPXV-BR-218 41917 20178572 212 Red receptor Cowpox virus strain GRI-90 Orthopoxvirus 1501 IFN-alpha/beta 584 CPXV-GRI-200 42857 30519568 B17R receptor Cowpox virus strain Germany 91-3 Orthopoxvirus 2214 IFN-alpha/beta 584 CPXV-GER91-200 56575 90660433 immuno- receptor globulin superfamily secreted glycoprotein Deerpox virus strain W-1170-84 Unclassified 1516 IFN-alpha/beta 584 DPV-W1170_84-145 45428 0 147b receptor Deerpox virus strain W-1170-84 Unclassified 1516 IFN-alpha/beta 584 DPV-W1170_84-146 45429 0 147a receptor Deerpox virus strain W-848-83 Unclassified 1515 IFN-alpha/beta 584 DPV-W848_83-145 45258 62637524 147a receptor Ectromelia virus strain Moscow Orthopoxvirus 1492 IFN-alpha/beta 584 ECTV-Mos-171 41090 22164601 166 receptor Ectromelia virus strain Naval Orthopoxvirus 1499 IFN-alpha/beta 584 ECTV-Nav-176 42431 0 194 receptor Goatpox virus strain G20-LKV Capripoxvirus 1514 IFN-alpha/beta 584 GTPV-G20LKV-134 45094 0 129 receptor Goatpox virus strain Pellor Capripoxvirus 1513 IFN-alpha/beta 584 GTPV-Pellor-132 44942 0 129 receptor Horsepox virus strain MNR-76 Orthopoxvirus 2230 IFN-alpha/beta 584 HSPV-MNR76-221 59858 111184388 HSPV195 receptor Lumpy skin disease virus strain Capripoxvirus 1488 IFN-alpha/beta 584 LSDV-Nee-137 40340 15150574 135 Neethling 2490 receptor Lumpy skin disease virus strain Capripoxvirus 1497 IFN-alpha/beta 584 LSDV-NW_LW-139 42073 22595670 135 Neethling Warmbaths LW receptor Lumpy skin disease virus strain Capripoxvirus 1498 IFN-alpha/beta 584 LSDV-LW1959-139 42233 22595829 135 Neethling vaccine LW 1959 receptor Monkeypox Virus strain Walter Orthopoxvirus 1502 IFN-alpha/beta 584 MPXV-WR267-168 43039 0 167 Reed 267 receptor Monkeypox virus strain COP-58 Orthopoxvirus 1520 IFN-alpha/beta 584 MPXV-COP58-167 46472 59858973 167 receptor Monkeypox virus strain Orthopoxvirus 1524 IFN-alpha/beta 584 MPXV- 47244 68449061 192 Congo_2003_358 receptor COG_2003_358-185 Monkeypox virus strain Orthopoxvirus 1525 IFN-alpha/beta 584 MPXV- 47444 68449465 192 Liberia_1970_184 receptor LBR_1970_184-185 Monkeypox virus strain Sierra Orthopoxvirus 1521 IFN-alpha/beta 584 MPXV-SLE-167 46649 58220637 167 Leone receptor Monkeypox virus strain Orthopoxvirus 1526 IFN-alpha/beta 584 MPXV- 47642 68449664 192 USA_2003_039 receptor USA_2003_039-185 Monkeypox virus strain Orthopoxvirus 1522 IFN-alpha/beta 584 MPXV- 46844 68448862 192 USA_2003_044 receptor USA 2003_044-185 Monkeypox virus strain Zaire Orthopoxvirus 1489 IFN-alpha/beta 584 MPXV-ZAR-180 40541 17975090 B16R receptor Monkeypox virus strain Orthopoxvirus 1523 IFN-alpha/beta 584 MPXV- 47044 68449264 192 Zaire_1979-005 receptor ZAR_1979_005-187 Myxoma virus strain Lausanne Leporipoxvirus 1479 IFN-alpha/beta 584 MYXV-Lau-140 38564 9633771 m135R receptor Rabbitpox virus strain Utrecht Orthopoxvirus 1494 IFN-alpha/beta 584 RPXV-Utr-181 41543 44971542 179 receptor Sheeppox virus strain A Capripoxvirus 1511 IFN-alpha/beta 584 SPPV-A-132 44641 0 129 receptor Sheeppox virus strain NISKHI Capripoxvirus 1512 IFN-alpha/beta 584 SPPV-NISKHI-131 44790 0 129 receptor Sheeppox virus strain TU- Capripoxvirus 1495 IFN-alpha/beta 584 SPPV-TU-132 41680 21492586 129 V02127 receptor Swinepox virus strain Nebraska Suipoxvirus 1490 IFN-alpha/beta 584 SWPV-Neb-133 40688 18640218 132 17077-99 receptor Tanapox virus strain Kenya Yatapoxvirus 3496 IFN-alpha/beta 584 TANV-KEN-141 67659 146746476 136R receptor Tanapox virus strain isolate TPV- Yatapoxvirus 3497 IFN-alpha/beta 584 TANV-COD-140 67752 146746632 136R RoC receptor Taterapox virus strain Dahomey Orthopoxvirus 2195 IFN-alpha/beta 584 TATV-DAH68-210 53128 113195387 IFN-alpha:beta- 1968 receptor receptor-like secreted glycoprotein Vaccinia virus strain 3737 Orthopoxvirus 1528 IFN-alpha/beta 584 VACV-3737-202 47990 88900816 188 receptor Vaccinia virus strain Acambis Orthopoxvirus 2161 IFN-alpha/beta 584 VACV-Acam2000- 51266 38349068 212 2000 receptor 210 Vaccinia virus strain Acarnbis 3 Orthopoxvirus 2162 IFN-alpha/beta 584 VACV-Acam3-212 51503 37551646 212 receptor Vaccinia virus strain Acambis Orthopoxvirus 1510 IFN-alpha/beta 584 VACV-Acam3000- 44503 47088513 187 3000 Modified Virus Ankara receptor 189 Vaccinia virus strain Orthopoxvirus 1485 IFN-alpha/beta 584 VACV-Cop-254 39779 335566 B19R Copenhagen receptor Vaccinia virus strain DUKE Orthopoxvirus 2458 IFN-alpha/beta 584 VACV-DUKE-210 63590 90819862 210 receptor Vaccinia virus strain MVA-I721 Orthopoxvirus 2696 IFN-alpha/beta 584 VACV-MVA_I721- 65280 0 187 receptor 066 Vaccinia virus strain Western Orthopoxvirus 1500 IFN-alpha/beta 584 VACV-WR-200 42639 66275997 200 Reserve receptor Variola major virus strain Orthopoxvirus 1481 IFN-alpha/beta 584 VARV-BGD75maj- 38945 439095 B17R Bangladesh 1975 receptor 184 Variola minor virus strain Garcia Orthopoxvirus 1482 IFN-alpha/beta 584 VARV-Gar_1966-199 39152 5830751 D9R 1966 receptor Variola virus strain Afghanistan Orthopoxvirus 2197 IFN-alpha/beta 584 VARV-AFG70-193 53537 109724232 glycoprotein 1970 Variolator 4 receptor Variola virus strain Bangladesh Orthopoxvirus 2216 IFN-alpha/beta 584 VARV-BGD74_shz- 56981 94484846 glycoprotein 1974 (Shahzaman) receptor 189 Variola virus strain Bangladesh Orthopoxvirus 2217 IFN-alpha/beta 584 VARV-BGD74_sol- 57179 94485044 glycoprotein 1974 (Solaiman) receptor 189 Variola virus strain Bangladesh Orthopoxvirus 2215 IFN-alpha/beta 584 VARV-BGD74_nur- 56783 94484648 glycoprotein 1974 (nur islam) receptor 189 Variola virus strain Bangladesh Orthopoxvirus 2198 IFN-alpha/beta 584 VARV-BGD75_Banu- 53739 109724435 glycoprotein 1975 v75-550 Banu receptor 192 Variola virus strain Benin, Orthopoxvirus 2224 IFN-alpha/beta 584 VARV-BEN68-198 58608 94483835 glycoprotein Dahomey 1968 (v68-59) receptor Variola virus strain Botswana Orthopoxvirus 2225 IFN-alpha/beta 584 VARV-BWA72-191 58810 94484038 glycoprotein 1972 (v72-143) receptor Variola virus strain Botswana Orthopoxvirus 2226 IFN-alpha/beta 584 VARV-BWA73-191 59012 94484241 glycoprotein 1973 (v73-225) receptor Variola virus strain Brazil 1966 Orthopoxvirus 2227 IFN-alpha/beta 584 VARV-BRA66-200 59223 94484448 glycoprotein (v66-39 Sao Paulo) receptor Variola virus strain China Horn Orthopoxvirus 2203 IFN-alpha/beta 584 VARV-CHN48-194 54354 109724638 glycoprotein 1948 Sabin Lab July 1948 receptor Variola virus strain Congo 1970 Orthopoxvirus 2229 IFN-alpha/beta 584 VARV-COG70_46- 59627 109724843 glycoprotein v70-46 Kinshasa receptor 192 Variola virus strain Congo 9 1970 Orthopoxvirus 2228 IFN-alpha/beta 584 VARV-COG70_227- 59425 94485244 glycoprotein (v74-227 Gispen) receptor 191 Variola virus strain Ethiopia 1972 Orthopoxvirus 2231 IFN-alpha/beta 584 VARV-ETH72_16- 60066 94485447 glycoprotein (Eth16 R14-1X-72 Addis) receptor 193 Variola virus strain Ethiopia 1972 Orthopoxvirus 2232 IFN-alpha/beta 584 VARV-ETH72_17- 60267 94485648 glycoprotein (Eth17 R14-1X-72 Addis) receptor 191 Variola virus strain Germany Orthopoxvirus 2233 IFN-alpha/beta 584 VARV-DEU58-191 60468 109725045 glycoprotein 1958 Heidelberg receptor Variola virus strain Guinea 1969 Orthopoxvirus 2234 IFN-alpha/beta 584 VARV-GIN69-196 60674 94485851 glycoprotein (005) receptor Variola virus strain India 1953 Orthopoxvirus 2238 IFN-alpha/beta 584 VARV-IND53_mad- 61481 94486054 glycoprotein (Kali-Muthu-M50 Madras) receptor 191 Variola virus strain India 1953 Orthopoxvirus 2239 IFN-alpha/beta 584 VARV-IND53_ndel- 61682 94486256 glycoprotein (New Delhi) receptor 191 Variola virus strain India 1964 Orthopoxvirus 2240 IFN-alpha/beta 584 VARV-IND64_vel4- 61888 109725251 glycoprotein 7124 Vellore receptor 195 Variola virus strain India 1964 Orthopoxvirus 2241 IFN-alpha/beta 584 VARV-IND64_vel5- 62092 109725456 immuno- 7125 Vellore receptor 194 globulin superfamily secreted glycoprotein Variola virus strain India 3 Major Orthopoxvirus 1483 IFN-alpha/beta 584 VARV-IND3_1967- 39353 9627709 B20R 1967 receptor 191 Variola virus strain Iran 1972 Orthopoxvirus 2235 IFN-alpha/beta 584 VARV-IRN72-193 60878 109725658 glycoprotein 2602 Tabriz receptor Variola virus strain Japan 1946 Orthopoxvirus 2243 IFN-alpha/beta 584 VARV-JPN46_yam- 62466 94486459 glycoprotein (Yamada MS-2(A) Tokyo) receptor 191 Variola virus strain Japan 1951 Orthopoxvirus 2244 IFN-alpha/beta 584 VARV-JPN51_hrpr- 62667 94486661 glycoprotein (Harper, Masterseed) receptor 190 Variola virus strain Japan 1951 Orthopoxvirus 2245 IFN-alpha/beta 584 VARV-JPN51_stwl- 62869 94486864 glycoprotein (Stillwell, Masterseed) receptor 191 Variola virus strain Korea 1947 Orthopoxvirus 2236 IFN-alpha/beta 584 VARV-KOR47-192 61080 94487067 glycoprotein (Lee, Masterseed) receptor Variola virus strain Kuwait 1967 Orthopoxvirus 2237 IFN-alpha/beta 584 VARV-KWT67-191 61281 94487269 glycoprotein (K1629) receptor Variola virus strain Nepal 1973 Orthopoxvirus 2221 IFN-alpha/beta 584 VARV-NPL73-192 57982 109725860 glycoprotein V73-175 receptor Variola virus strain Niger 1969 Orthopoxvirus 2222 IFN-alpha/beta 584 VARV-NER69-198 58191 94487472 glycoprotein (001, importation from Nigeria) receptor Variola virus strain Sierra Leone Orthopoxvirus 2223 IFN-alpha/beta 584 VARV-SLE68-197 58399 94488080 glycoprotein 1969 (V68-258) receptor Variola virus strain Somalia 1977 Orthopoxvirus 2218 IFN-alpha/beta 584 VARV-SOM77_1252- 57378 94488282 glycoprotein (V77-1252) receptor 190 Variola virus strain Somalia 1977 Orthopoxvirus 2219 IFN-alpha/beta 584 VARV-SOM77_1605- 57578 94488482 glycoprotein (V77-1605) receptor 190 Variola virus strain Somalia 1977 Orthopoxvirus 2220 IFN-alpha/beta 584 VARV-SOM77_ali- 57780 109726268 glycoprotein V77-2479 receptor 192 Variola virus strain South Africa Orthopoxvirus 2210 IFN-alpha/beta 584 VARV-ZAF65_102- 55763 94487675 glycoprotein 1965 (102 Natal, Ingwavuma) receptor 191 Variola virus strain South Africa Orthopoxvirus 2211 IFN-alpha/beta 584 VARV-ZAF65_103- 55964 94487876 glycoprotein 1965 (103 Tvaal, Nelspruit) receptor 191 Variola virus strain Sudan 1947 Orthopoxvirus 2212 IFN-alpha/beta 584 VARV-SDN47_jub- 56164 94488682 immuno- (Juba) receptor 190 globulin superfamily secreted glycoprotein Variola virus strain Sudan 1947 Orthopoxvirus 2213 IFN-alpha/beta 584 VARV-SDN47_rum- 56365 94488884 glycoprotein (Rumbec) receptor 191 Variola virus strain Sumatra 1970 Orthopoxvirus 2208 IFN-alpha/beta 584 VARV-SUM70_222- 55362 109726471 glycoprotein V70-222 receptor 192 Variola virus strain Sumatra 1970 Orthopoxvirus 2209 IFN-alpha/beta 584 VARV-SUM70_228- 55562 94489084 glycoprotein V70-228 receptor 190 Variola virus strain Syria 1972 Orthopoxvirus 2206 IFN-alpha/beta 584 VARV-SYR72-193 54959 109726675 glycoprotein V72-199 receptor Variola virus strain Tanzania Orthopoxvirus 2207 IFN-alpha/beta 584 VARV-TZA65-191 55160 94489282 glycoprotein 1965 kembula receptor Variola virus strain United Orthopoxvirus 2204 IFN-alpha/beta 584 VARV-GBR44_harv- 54557 94489485 glycoprotein Kingdom 1946 Harvey receptor 192 Variola virus strain United Orthopoxvirus 2205 IFN-alpha/beta 584 VARV-GBR46_hind- 54757 94489686 glycoprotein Kingdom 1946 Hinden receptor 190 (Middlesex) Variola virus strain United Orthopoxvirus 2202 IFN-alpha/beta 584 VARV-GBR47_hig- 54150 94489885 glycoprotein Kingdom 1947 Higgins receptor 191 (Staffordshire) Variola virus strain United Orthopoxvirus 2200 IFN-alpha/beta 584 VARV-GBR52_but- 53948 94490092 glycoprotein Kingdom 1952 Butler receptor 200 Variola virus strain Yugoslavia Orthopoxvirus 2196 IFN-alpha/beta 584 VARV-YUG72-191 53334 94490295 glycoprotein 1972 V72-164 receptor Yaba-like Disease Virus strain Yatapoxvirus 1487 IFN-alpha/beta 584 YLDV-Davis-139 40188 12085119 136R Davis receptor

TABLE 10 Viral Orthologous Clusters V2.0 (VOCs) Semaphorin Gene Results Table Ortholog Genome Group Ortholog Gene Genbank Genome name Genus id Name Group ID Gene number id id Genbank name Camelpox virus strain CMS Orthopoxvirus 1493 Semaphorin 295 CMLV-CMS-201 41297 19718129 156R Camelpox virus strain M96 Orthopoxvirus 1491 Semaphorin 295 CMLV-M96-161 40867 18640393 159 Canarypox virus strain ATCC Avipoxvirus 1506 Semaphorin 295 CNPV-VR111-065 43538 40556003  65 VR111 Cowpox virus strain Brighton Red Orthopoxvirus 1496 Semaphorin 295 CPXV-BR-182 41881 20178538 176 Cowpox virus strain GRI-90 Orthopoxvirus 1501 Semaphorin 295 CPXV-GRI-165 42822 30519533 A41R Cowpox virus strain Germany 91-3 Orthopoxvirus 2214 Semaphorin 295 CPXV-GER91-164 56539 90660397 semaphorin- like protein Ectromelia virus strain Moscow Orthopoxvirus 1492 Semaphorin 295 ECTV-Mos-144 41063 22164745 139 Ectromelia virus strain Naval Orthopoxvirus 1499 Semaphorin 295 ECTV-Nav-147 42402 0 161 Fowlpox virus strain HP1-438 Avipoxvirus 1509 Semaphorin 295 FWPV-HP1_438-046 44119 41023339 fp9.047 Munich Fowlpox virus strain Iowa Avipoxvirus 1476 Semaphorin 295 FWPV-Iowa-047 37779 9634717  47 Horsepox virus strain MNR-76 Orthopoxvirus 2230 Semaphorin 295 HSPV-MNR76-183 59820 111184350 HSPV161 Rabbitpox virus strain Utrecht Orthopoxvirus 1494 Semaphorin 295 RPXV-Utr-149 41511 44971510 147 Taterapox virus strain Dahomey Orthopoxvirus 2195 Semaphorin 295 TATV-DAH68-164 53082 113195341 semaphorin- 1968 like protein Vaccinia virus strain 3737 Orthopoxvirus 1528 Semaphorin 295 VACV-3737-165 47953 88900781 202 Vaccinia virus strain Acambis 2000 Orthopoxvirus 2161 Semaphorin 295 VACV-Acam2000-172 51228 38349030 174 Vaccinia virus strain Acambis 2000 Orthopoxvirus 2161 Semaphorin 295 VACV-Acam2000-173 51229 38349031 175 Vaccinia virus strain Acambis 3 Orthopoxvirus 2162 Semaphorin 295 VACV-Acam3-174 51465 37551608 174 Vaccinia virus strain Acambis 3 Orthopoxvirus 2162 Semaphorin 295 VACV-Acam3-175 51466 37551609 175 Vaccinia virus strain Acambis 3000 Orthopoxvirus 1510 Semaphorin 295 VACV-Acam3000-154 44468 47088478 152 Modified Virus Ankara Vaccinia virus strain Acambis 3000 Orthopoxvirus 1510 Semaphorin 295 VACV-Acam3000-155 44469 47088479 153 Modified Virus Ankara Vaccinia virus strain Copenhagen Orthopoxvirus 1485 Semaphorin 295 VACV-Cop-205 39730 335517 A39R Vaccinia virus strain DUKE Orthopoxvirus 2458 Semaphorin 295 VACV-DUKE-171 63551 90819823 171 Vaccinia virus strain DUKE Orthopoxvirus 2458 Semaphorin 295 VACV-DUKE-172 63552 90819824 172 Vaccinia virus strain LC16m8 Orthopoxvirus 1517 Semaphorin 295 VACV-LC16m8-219 45672 56713558 m8209R Vaccinia virus strain LC16mO Orthopoxvirus 1518 Semaphorin 295 VACV-LC16mO-219 45956 56713842 mO209R Vaccinia virus strain Lister Orthopoxvirus 1519 Semaphorin 295 VACV-Lister-219 46240 0 m8209R Vaccinia virus strain Orthopoxvirus 2659 Semaphorin 295 VACV- 64493 88854236 List156 Lister_VACV107 Lister_VACV107-160 Vaccinia virus strain MVA-I721 Orthopoxvirus 2696 Semaphorin 295 VACV-MVA_I721-126 65339 0 153 Vaccinia virus strain MVA-I721 Orthopoxvirus 2696 Semaphorin 295 VACV-MVA_I721-127 65340 0 152 Vaccinia virus strain Western Orthopoxvirus 1500 Semaphorin 295 VACV-WR-163 42602 66275960 163 Reserve Vaccinia virus strain Western Orthopoxvirus 1500 Semaphorin 295 VACV-WR-164 42603 66275961 164 Reserve Variola major virus strain Orthopoxvirus 1481 Semaphorin 295 VARV-BGD75maj- 38913 439063 A42R Bangladesh 1975 152 Variola major virus strain Orthopoxvirus 1481 Semaphorin 295 VARV-BGD75maj- 38914 439064 A43R Bangladesh 1975 153 Variola minor virus strain Garcia Orthopoxvirus 1482 Semaphorin 295 VARV-Gar_1966-157 39110 5830709 A45R 1966 Variola minor virus strain Garcia Orthopoxvirus 1482 Semaphorin 295 VARV-Gar_1966-158 39111 5830710 A46R 1966 Variola minor virus strain Garcia Orthopoxvirus 1482 Semaphorin 295 VARV-Gar_1966-159 39112 5830711 A47R 1966 Variola virus strain Afghanistan Orthopoxvirus 2197 Semaphorin 295 VARV-AFG70-153 53497 109724192 semaphorin- 1970 Variolator 4 like protein Variola virus strain Afghanistan Orthopoxvirus 2197 Semaphorin 295 VARV-AFG70-154 53498 109724193 semaphorin- 1970 Variolator 4 like protein Variola virus strain Afghanistan Orthopoxvirus 2197 Semaphorin 295 VARV-AFG70-155 53499 109724194 semaphorin- 1970 Variolator 4 like protein Variola virus strain Bangladesh Orthopoxvirus 2216 Semaphorin 295 VARV-BGD74_shz- 56945 94484810 semaphorin- 1974 (Shahzaman) 153 like protein Variola virus strain Bangladesh Orthopoxvirus 2216 Semaphorin 295 VARV-BGD74_shz- 56946 94484811 semaphorin- 1974 (Shahzaman) 154 like protein Variola virus strain Bangladesh Orthopoxvirus 2217 Semaphorin 295 VARV-BGD74_sol- 57143 94485008 semaphorin- 1974 (Solaiman) 153 like protein Variola virus strain Bangladesh Orthopoxvirus 2217 Semaphorin 295 VARV-BGD74_sol- 57144 94485009 semaphorin- 1974 (Solaiman) 154 like protein Variola virus strain Bangladesh Orthopoxvirus 2215 Semaphorin 295 VARV-BGD74_nur- 56747 94484612 semaphorin- 1974 (nur islam) 153 like protein Variola virus strain Bangladesh Orthopoxvirus 2215 Semaphorin 295 VARV-BGD74_nur- 56748 94484613 semaphorin- 1974 (nur islam) 154 like protein Variola virus strain Bangladesh Orthopoxvirus 2215 Semaphorin 295 VARV-BGD74_nur- 56749 94484614 type-II 1974 (nur islam) 155 membrane protein Variola virus strain Bangladesh Orthopoxvirus 2198 Semaphorin 295 VARV-BGD75_Banu- 53700 109724396 semaphorin- 1975 v75-550 Banu 153 like protein Variola virus strain Bangladesh Orthopoxvirus 2198 Semaphorin 295 VARV-BGD75_Banu- 53701 109724397 semaphorin- 1975 v75-550 Banu 154 like protein Variola virus strain Benin, Dahomey Orthopoxvirus 2224 Semaphorin 295 VARV-BEN68-154 58564 94483794 semaphorin- 1968 (v68-59) like protein Variola virus strain Benin, Dahomey Orthopoxvirus 2224 Semaphorin 295 VARV-BEN68-155 58565 94483795 semaphorin- 1968 (v68-59) like protein Variola virus strain Benin, Dahomey Orthopoxvirus 2224 Semaphorin 295 VARV-BEN68-156 58566 94483796 semaphorin- 1968 (v68-59) like protein Variola virus strain Botswana 1972 Orthopoxvirus 2225 Semaphorin 295 VARV-BWA72-153 58772 94484000 semaphorin- (v72-143) like protein Variola virus strain Botswana 1972 Orthopoxvirus 2225 Semaphorin 295 VARV-BWA72-154 58773 94484001 semaphorin- (v72-143) like protein Variola virus strain Botswana 1973 Orthopoxvirus 2226 Semaphorin 295 VARV-BWA73-153 58974 94484203 semaphorin- (v73-225) like protein Variola virus strain Botswana 1973 Orthopoxvirus 2226 Semaphorin 295 VARV-BWA73-154 58975 94484204 semaphorin- (v73-225) like protein Variola virus strain Brazil 1966 (v66- Orthopoxvirus 2227 Semaphorin 295 VARV-BRA66-157 59180 94484408 semaphorin- 39 Sao Paulo) like protein Variola virus strain Brazil 1966 (v66- Orthopoxvirus 2227 Semaphorin 295 VARV-BRA66-158 59181 94484409 semaphorin- 39 Sao Paulo) like protein Variola virus strain Brazil 1966 (v66- Orthopoxvirus 2227 Semaphorin 295 VARV-BRA66-159 59182 94484410 semaphorin- 39 Sao Paulo) like protein Variola virus strain China Horn 1948 Orthopoxvirus 2203 Semaphorin 295 VARV-CHN48-153 54313 109724598 semaphorin- Sabin Lab July 1948 like protein Variola virus strain China Horn 1948 Orthopoxvirus 2203 Semaphorin 295 VARV-CHN48-154 54314 109724599 semaphorin- Sabin Lab July 1948 like protein Variola virus strain China Horn 1948 Orthopoxvirus 2203 Semaphorin 295 VARV-CHN48-155 54315 109724600 semaphorin- Sabin Lab July 1948 like protein Variola virus strain Congo 1970 v70- Orthopoxvirus 2229 Semaphorin 295 VARV-COG70_46- 59588 109724803 semaphorin- 46 Kinshasa 153 like protein Variola virus strain Congo 1970 v70- Orthopoxvirus 2229 Semaphorin 295 VARV-COG70_46- 59589 109724804 semaphorin- 46 Kinshasa 154 like protein Variola virus strain Congo 9 1970 Orthopoxvirus 2228 Semaphorin 295 VARV-COG70_227- 59387 94485206 semaphorin- (v74-227 Gispen) 153 like protein Variola virus strain Congo 9 1970 Orthopoxvirus 2228 Semaphorin 295 VARV-COG70_227- 59388 94485207 semaphorin- (v74-227 Gispen) 154 like protein Variola virus strain Ethiopia 1972 Orthopoxvirus 2231 Semaphorin 295 VARV-ETH72_16-154 60027 94485408 semaphorin- (Eth16 R14-1X-72 Addis) like protein Variola virus strain Ethiopia 1972 Orthopoxvirus 2231 Semaphorin 295 VARV-ETH72_16-155 60028 94485409 semaphorin- (Eth16 R14-1X-72 Addis) like protein Variola virus strain Ethiopia 1972 Orthopoxvirus 2232 Semaphorin 295 VARV-ETH72_17-154 60230 94485611 semaphorin- (Eth17 R14-1X-72 Addis) like protein Variola virus strain Ethiopia 1972 Orthopoxvirus 2232 Semaphorin 295 VARV-ETH72_17-155 60231 94485612 semaphorin- (Eth17 R14-1X-72 Addis) like protein Variola virus strain Germany 1958 Orthopoxvirus 2233 Semaphorin 295 VARV-DEU58-152 60429 109725006 semaphorin- Heidelberg like protein Variola virus strain Germany 1958 Orthopoxvirus 2233 Semaphorin 295 VARV-DEU58-153 60430 109725007 semaphorin- Heidelberg like protein Variola virus strain Guinea 1969 Orthopoxvirus 2234 Semaphorin 295 VARV-GIN69-153 60631 94485811 semaphorin- (005) like protein Variola virus strain Guinea 1969 Orthopoxvirus 2234 Semaphorin 295 VARV-GIN69-154 60632 94485812 semaphorin- (005) like protein Variola virus strain Guinea 1969 Orthopoxvirus 2234 Semaphorin 295 VARV-GIN69-155 60633 94485813 semaphorin- (005) like protein Variola virus strain India 1953 (Kali- Orthopoxvirus 2238 Semaphorin 295 VARV-IND53_mad- 61443 94486016 semaphorin- Muthu-M50 Madras) 153 like protein Variola virus strain India 1953 (Kali- Orthopoxvirus 2238 Semaphorin 295 VARV-IND53_mad- 61444 94486017 semaphorin- Muthu-M50 Madras) 154 like protein Variola virus strain India 1953 (Kali- Orthopoxvirus 2238 Semaphorin 295 VARV-IND53_mad- 61445 94486018 semaphorin- Muthu-M50 Madras) 155 like protein Variola virus strain India 1953 (New Orthopoxvirus 2239 Semaphorin 295 VARV-IND53_ndel- 61643 94486217 semaphorin- Delhi) 152 like protein Variola virus strain India 1953 (New Orthopoxvirus 2239 Semaphorin 295 VARV-IND53_ndel- 61644 94486218 semaphorin- Delhi) 153 like protein Variola virus strain India 1953 (New Orthopoxvirus 2239 Semaphorin 295 VARV-IND53_ndel- 61645 94486219 semaphorin- Delhi) 154 like protein Variola virus strain India 1964 7124 Orthopoxvirus 2240 Semaphorin 295 VARV-IND64_vel4- 61847 109725210 semaphorin- Vellore 154 like protein Variola virus strain India 1964 7124 Orthopoxvirus 2240 Semaphorin 295 VARV-IND64_vel4- 61848 109725211 semaphorin- Vellore 155 like protein Variola virus strain India 1964 7124 Orthopoxvirus 2240 Semaphorin 295 VARV-IND64_vel4- 61849 109725212 semaphorin- Vellore 156 like protein Variola virus strain India 1964 7125 Orthopoxvirus 2241 Semaphorin 295 VARV-IND64_vel5- 62051 109725415 semaphorin- Vellore 153 like protein Variola virus strain India 1964 7125 Orthopoxvirus 2241 Semaphorin 295 VARV-IND64_vel5- 62052 109725416 semaphorin- Vellore 154 like protein Variola virus strain India 1964 7125 Orthopoxvirus 2241 Semaphorin 295 VARV-IND64_vel5- 62053 109725417 semaphorin- Vellore 155 like protein Variola virus strain India 3 Major Orthopoxvirus 1483 Semaphorin 295 VARV-IND3_1967- 39313 9627669 A42R 1967 151 Variola virus strain India 3 Major Orthopoxvirus 1483 Semaphorin 295 VARV-IND3_1967- 39314 9627670 A43R 1967 152 Variola virus strain India 3 Major Orthopoxvirus 1483 Semaphorin 295 VARV-IND3_1967- 39315 9627671 A44R 1967 153 Variola virus strain Iran 1972 2602 Orthopoxvirus 2235 Semaphorin 295 VARV-IRN72-153 60838 109725618 semaphorin- Tabriz like protein Variola virus strain Iran 1972 2602 Orthopoxvirus 2235 Semaphorin 295 VARV-IRN72-154 60839 109725619 semaphorin- Tabriz like protein Variola virus strain Iran 1972 2602 Orthopoxvirus 2235 Semaphorin 295 VARV-IRN72-155 60840 109725620 semaphorin- Tabriz like protein Variola virus strain Japan 1946 Orthopoxvirus 2243 Semaphorin 295 VARV-JPN46_yam- 62427 94486420 semaphorin- (Yamada MS-2(A) Tokyo) 152 like protein Variola virus strain Japan 1946 Orthopoxvirus 2243 Semaphorin 295 VARV-JPN46_yam- 62428 94486421 semaphorin- (Yamada MS-2(A) Tokyo) 153 like protein Variola virus strain Japan 1946 Orthopoxvirus 2243 Semaphorin 295 VARV-JPN46_yam- 62429 94486422 semaphorin- (Yamada MS-2(A) Tokyo) 154 like protein Variola virus strain Japan 1946 Orthopoxvirus 2243 Semaphorin 295 VARV-JPN46_yam- 62430 94486423 type-II (Yamada MS-2(A) Tokyo) 155 membrane protein Variola virus strain Japan 1951 Orthopoxvirus 2244 Semaphorin 295 VARV-JPN51_hrpr- 62629 94486623 semaphorin- (Harper, Masterseed) 152 like protein Variola virus strain Japan 1951 Orthopoxvirus 2244 Semaphorin 295 VARV-JPN51_hrpr- 62630 94486624 semaphorin- (Harper, Masterseed) 153 like protein Variola virus strain Japan 1951 Orthopoxvirus 2244 Semaphorin 295 VARV-JPN51_hrpr- 62631 94486625 semaphorin- (Harper, Masterseed) 154 like protein Variola virus strain Japan 1951 Orthopoxvirus 2244 Semaphorin 295 VARV-JPN51_hrpr- 62632 94486626 type-II (Harper, Masterseed) 155 membrane protein Variola virus strain Japan 1951 Orthopoxvirus 2245 Semaphorin 295 VARV-JPN51_stwl- 62830 94486825 semaphorin- (Stillwell, Masterseed) 152 like protein Variola virus strain Japan 1951 Orthopoxvirus 2245 Semaphorin 295 VARV-JPN51_stwl- 62831 94486826 semaphorin- (Stillwell, Masterseed) 153 like protein Variola virus strain Japan 1951 Orthopoxvirus 2245 Semaphorin 295 VARV-JPN51_stwl- 62832 94486827 semaphorin- (Stillwell, Masterseed) 154 like protein Variola virus strain Japan 1951 Orthopoxvirus 2245 Semaphorin 295 VARV-JPN51_stwl- 62833 94486828 type-II (Stillwell, Masterseed) 155 membrane protein Variola virus strain Korea 1947 Orthopoxvirus 2236 Semaphorin 295 VARV-KOR47-153 61041 94487028 semaphorin- (Lee, Masterseed) like protein Variola virus strain Korea 1947 Orthopoxvirus 2236 Semaphorin 295 VARV-KOR47-154 61042 94487029 semaphorin- (Lee, Masterseed) like protein Variola virus strain Korea 1947 Orthopoxvirus 2236 Semaphorin 295 VARV-KOR47-155 61043 94487030 semaphorin- (Lee, Masterseed) like protein Variola virus strain Korea 1947 Orthopoxvirus 2236 Semaphorin 295 VARV-KOR47-156 61044 94487031 type-II (Lee, Masterseed) membrane protein Variola virus strain Kuwait 1967 Orthopoxvirus 2237 Semaphorin 295 VARV-KWT67-153 61243 94487231 semaphorin- (K1629) like protein Variola virus strain Kuwait 1967 Orthopoxvirus 2237 Semaphorin 295 VARV-KWT67-154 61244 94487232 semaphorin- (K1629) like protein Variola virus strain Kuwait 1967 Orthopoxvirus 2237 Semaphorin 295 VARV-KWT67-155 61245 94487233 semaphorin- (K1629) like protein Variola virus strain Nepal 1973 V73- Orthopoxvirus 2221 Semaphorin 295 VARV-NPL73-153 57943 109725822 semaphorin- 175 like protein Variola virus strain Nepal 1973 V73- Orthopoxvirus 2221 Semaphorin 295 VARV-NPL73-154 57944 109725823 semaphorin- 175 like protein Variola virus strain Nepal 1973 V73- Orthopoxvirus 2221 Semaphorin 295 VARV-NPL73-155 57945 109725824 type-II 175 membrane protein Variola virus strain Niger 1969 (001, Orthopoxvirus 2222 Semaphorin 295 VARV-NER69-155 58148 94487432 semaphorin- importation from Nigeria) like protein Variola virus strain Niger 1969 (001, Orthopoxvirus 2222 Semaphorin 295 VARV-NER69-156 58149 94487433 semaphorin- importation from Nigeria) like protein Variola virus strain Niger 1969 (001, Orthopoxvirus 2222 Semaphorin 295 VARV-NER69-157 58150 94487434 semaphorin- importation from Nigeria) like protein Variola virus strain Sierra Leone Orthopoxvirus 2223 Semaphorin 295 VARV-SLE68-154 58356 94488040 semaphorin- 1969 (V68-258) like protein Variola virus strain Sierra Leone Orthopoxvirus 2223 Semaphorin 295 VARV-SLE68-155 58357 94488041 semaphorin- 1969 (V68-258) like protein Variola virus strain Sierra Leone Orthopoxvirus 2223 Semaphorin 295 VARV-SLE68-156 58358 94488042 semaphorin- 1969 (V68-258) like protein Variola virus strain Somalia 1977 Orthopoxvirus 2218 Semaphorin 295 VARV-SOM77_1252- 57341 94488245 semaphorin- (V77-1252) 153 like protein Variola virus strain Somalia 1977 Orthopoxvirus 2218 Semaphorin 295 VARV-SOM77_1252- 57342 94488246 semaphorin- (V77-1252) 154 like protein Variola virus strain Somalia 1977 Orthopoxvirus 2218 Semaphorin 295 VARV-SOM77_1252- 57343 94488247 type-II (V77-1252) 155 membrane protein Variola virus strain Somalia 1977 Orthopoxvirus 2219 Semaphorin 295 VARV-SOM77_1605- 57541 94488445 semaphorin- (V77-1605) 153 like protein Variola virus strain Somalia 1977 Orthopoxvirus 2219 Semaphorin 295 VARV-SOM77_1605- 57542 94488446 semaphorin- (V77-1605) 154 like protein Variola virus strain Somalia 1977 Orthopoxvirus 2219 Semaphorin 295 VARV-SOM77_1605- 57543 94488447 type-II (V77-1605) 155 membrane protein Variola virus strain Somalia 1977 Orthopoxvirus 2220 Semaphorin 295 VARV-SOM77_ali- 57741 109726229 semaphorin- V77-2479 153 like protein Variola virus strain Somalia 1977 Orthopoxvirus 2220 Semaphorin 295 VARV-SOM77_ali- 57742 109726230 semaphorin- V77-2479 154 like protein Variola virus strain Somalia 1977 Orthopoxvirus 2220 Semaphorin 295 VARV-SOM77_ali- 57743 109726231 type-II V77-2479 155 membrane protein Variola virus strain South Africa Orthopoxvirus 2210 Semaphorin 295 VARV-ZAF65_102- 55725 94487637 semaphorin- 1965 (102 Natal, Ingwavuma) 153 like protein Variola virus strain South Africa Orthopoxvirus 2210 Semaphorin 295 VARV-ZAF65_102- 55726 94487638 semaphorin- 1965 (102 Natal, Ingwavuma) 154 like protein Variola virus strain South Africa Orthopoxvirus 2210 Semaphorin 295 VARV-ZAF65_102- 55727 94487639 type-II 1965 (102 Natal, Ingwavuma) 155 membrane protein Variola virus strain South Africa Orthopoxvirus 2211 Semaphorin 295 VARV-ZAF65_103- 55926 94487838 semaphorin- 1965 (103 Tvaal, Nelspruit) 153 like protein Variola virus strain South Africa Orthopoxvirus 2211 Semaphorin 295 VARV-ZAF65_103- 55927 94487839 semaphorin- 1965 (103 Tvaal, Nelspruit) 154 like protein Variola virus strain South Africa Orthopoxvirus 2211 Semaphorin 295 VARV-ZAF65_103- 55928 94487840 type-II 1965 (103 Tvaal, Nelspruit) 155 membrane protein Variola virus strain Sudan 1947 Orthopoxvirus 2212 Semaphorin 295 VARV-SDN47_jub- 56127 94488645 semaphorin- (Juba) 153 like protein Variola virus strain Sudan 1947 Orthopoxvirus 2212 Semaphorin 295 VARV-SDN47_jub- 56128 94488646 semaphorin- (Juba) 154 like protein Variola virus strain Sudan 1947 Orthopoxvirus 2213 Semaphorin 295 VARV-SDN47_rum- 56327 94488846 semaphorin- (Rumbec) 153 like protein Variola virus strain Sudan 1947 Orthopoxvirus 2213 Semaphorin 295 VARV-SDN47_rum- 56328 94488847 semaphorin- (Rumbec) 154 like protein Variola virus strain Sumatra 1970 Orthopoxvirus 2208 Semaphorin 295 VARV-SUM70_222- 55321 109726430 semaphorin- V70-222 151 like protein Variola virus strain Sumatra 1970 Orthopoxvirus 2208 Semaphorin 295 VARV-SUM70_222- 55322 109726431 semaphorin- V70-222 152 like protein Variola virus strain Sumatra 1970 Orthopoxvirus 2208 Semaphorin 295 VARV-SUM70_222- 55323 109726432 semaphorin- V70-222 153 like protein Variola virus strain Sumatra 1970 Orthopoxvirus 2209 Semaphorin 295 VARV-SUM70_228- 55523 94489045 semaphorin- V70-228 151 like protein Variola virus strain Sumatra 1970 Orthopoxvirus 2209 Semaphorin 295 VARV-SUM70_228- 55524 94489046 semaphorin- V70-228 152 like protein Variola virus strain Sumatra 1970 Orthopoxvirus 2209 Semaphorin 295 VARV-SUM70_228- 55525 94489047 semaphorin- V70-228 153 like protein Variola virus strain Syria 1972 V72- Orthopoxvirus 2206 Semaphorin 295 VARV-SYR72-153 54919 109726635 semaphorin- 199 like protein Variola virus strain Syria 1972 V72- Orthopoxvirus 2206 Semaphorin 295 VARV-SYR72-154 54920 109726636 semaphorin- 199 like protein Variola virus strain Syria 1972 V72- Orthopoxvirus 2206 Semaphorin 295 VARV-SYR72-155 54921 109726637 semaphorin- 199 like protein Variola virus strain Tanzania 1965 Orthopoxvirus 2207 Semaphorin 295 VARV-TZA65-153 55122 94489246 semaphorin- kembula like protein Variola virus strain Tanzania 1965 Orthopoxvirus 2207 Semaphorin 295 VARV-TZA65-154 55123 94489247 semaphorin- kembula like protein Variola virus strain Tanzania 1965 Orthopoxvirus 2207 Semaphorin 295 VARV-TZA65-155 55124 94489248 type-II kembula membrane protein Variola virus strain United Kingdom Orthopoxvirus 2204 Semaphorin 295 VARV-GBR44_harv- 54518 94489446 semaphorin- 1946 Harvey 153 like protein Variola virus strain United Kingdom Orthopoxvirus 2204 Semaphorin 295 VARV-GBR44_harv- 54519 94489447 semaphorin- 1946 Harvey 154 like protein Variola virus strain United Kingdom Orthopoxvirus 2204 Semaphorin 295 VARV-GBR44_harv- 54520 94489448 semaphorin- 1946 Harvey 155 like protein Variola virus strain United Kingdom Orthopoxvirus 2205 Semaphorin 295 VARV-GBR46_hind- 54719 94489648 semaphorin- 1946 Hinden (Middlesex) 152 like protein Variola virus strain United Kingdom Orthopoxvirus 2205 Semaphorin 295 VARV-GBR46_hind- 54720 94489649 semaphorin- 1946 Hinden (Middlesex) 153 like protein Variola virus strain United Kingdom Orthopoxvirus 2205 Semaphorin 295 VARV-GBR46_hind- 54721 94489650 semaphorin- 1946 Hinden (Middlesex) 154 like protein Variola virus strain United Kingdom Orthopoxvirus 2202 Semaphorin 295 VARV-GBR47_hig- 54112 94489848 semaphorin- 1947 Higgins (Staffordshire) 153 like protein Variola virus strain United Kingdom Orthopoxvirus 2202 Semaphorin 295 VARV-GBR47_hig- 54113 94489849 semaphorin- 1947 Higgins (Staffordshire) 154 like protein Variola virus strain United Kingdom Orthopoxvirus 2200 Semaphorin 295 VARV-GBR52_but- 53905 94490052 semaphorin- 1952 Butler 157 like protein Variola virus strain United Kingdom Orthopoxvirus 2200 Semaphorin 295 VARV-GBR52_but- 53906 94490053 semaphorin- 1952 Butler 158 like protein Variola virus strain United Kingdom Orthopoxvirus 2200 Semaphorin 295 VARV-GBR52_but- 53907 94490054 semaphorin- 1952 Butler 159 like protein Variola virus strain Yugoslavia 1972 Orthopoxvirus 2196 Semaphorin 295 VARV-YUG72-153 53296 94490257 semaphorin- V72-164 like protein Variola virus strain Yugoslavia 1972 Orthopoxvirus 2196 Semaphorin 295 VARV-YUG72-154 53297 94490258 semaphorin- V72-164 like protein Variola virus strain Yugoslavia 1972 Orthopoxvirus 2196 Semaphorin 295 VARV-YUG72-155 53298 94490259 semaphorin- V72-164 like protein

TABLE 11 Viral Orthologous Clusters V2.0 (VOCs) TNF receptor Gene Results Table Ortholog Ortholog Genome Group Group Gene Genbank Genbank Genome name Genus id Name ID Gene number id id name Camelpox virus strain CMS Orthopoxvirus 1493 TNF receptor 642 CMLV-CMS- 41098 19717931 2L (CrmB) 002 Camelpox virus strain CMS Orthopoxvirus 1493 TNF-alpha 742 CMLV-CMS- 41105 19717938 7L receptor (CPXV- 009 GRI-K3R) Camelpox virus strain CMS Orthopoxvirus 1493 TNF receptor 642 CMLV-CMS- 41361 19718193 R (CrmB) 265 Camelpox virus strain M96 Orthopoxvirus 1491 TNF receptor 642 CMLV-M96- 40708 18640447  2 (CrmB) 002 Camelpox virus strain M96 Orthopoxvirus 1491 TNF-alpha 742 CMLV-M96- 40713 18640241  7 receptor (CPXV- 007 GRI-K3R) Camelpox virus strain M96 Orthopoxvirus 1491 TNF receptor 642 CMLV-M96- 40918 18640444 210 (CrmB) 212 Canarypox virus strain ATCC VR111 Avipoxvirus 1506 TNF receptor 642 CNPV-VR111- 43559 40556024  86 (CrmB) 086 Cowpox virus strain Brighton Red Orthopoxvirus 1496 TNF receptor 642 CPXV-BR- 41704 20178588  5 (CrmB) 005 Cowpox virus strain Brighton Red Orthopoxvirus 1496 TNF receptor 642 CPXV-BR- 41713 20178382 014f (CrmB) 014 Cowpox virus strain Brighton Red Orthopoxvirus 1496 TNF receptor 712 CPXV-BR- 41896 20178552 191 (CrmC) 197 Cowpox virus strain Brighton Red Orthopoxvirus 1496 TNF receptor 752 CPXV-BR- 41926 20178580 221 (CrmD) 227 Cowpox virus strain Brighton Red Orthopoxvirus 1496 TNF receptor 642 CPXV-BR- 41931 20178584 226 (CrmB) 232 Cowpox virus strain GRI-90 Orthopoxvirus 1501 TNF receptor 642 CPXV-GRI- 42659 30519407 D2L (CrmB) 002 Cowpox virus strain GRI-90 Orthopoxvirus 1501 TNF receptor 642 CPXV-GRI- 42669 1808601 D12L (CrmB) 012 Cowpox virus strain GRI-90 Orthopoxvirus 1501 TNF receptor 712 CPXV-GRI- 42837 30519548 A56R (CrmC) 180 Cowpox virus strain GRI-90 Orthopoxvirus 1501 TNF receptor 752 CPXV-GRI- 42864 30519575 K2R (CrmD) 207 Cowpox virus strain GRI-90 Orthopoxvirus 1501 TNF-alpha 742 CPXV-GRI- 42865 30519576 K3R receptor (CPXV- 208 GRI-K3R) Cowpox virus strain GRI-90 Orthopoxvirus 1501 TNF receptor 642 CPXV-GRI- 42870 30519581 I4R (CrmB) 213 Cowpox virus strain Germany 91-3 Orthopoxvirus 2214 TNF receptor 642 CPXV- 56377 90660235 TNF-alpha- (CrmB) GER91-002 receptor-like protein Cowpox virus strain Germany 91-3 Orthopoxvirus 2214 TNF receptor 642 CPXV- 56387 90660245 TNF-alpha- (CrmB) GER91-012 receptor-like protein Cowpox virus strain Germany 91-3 Orthopoxvirus 2214 TNF receptor 712 CPXV- 56554 90660412 secreted TNF- (CrmC) GER91-179 receptor-like protein Cowpox virus strain Germany 91-3 Orthopoxvirus 2214 TNF receptor 752 CPXV- 56584 90660442 Crm-B (CrmD) GER91-209 secreted TNF- alpha- receptor- like protein Cowpox virus strain Germany 91-3 Orthopoxvirus 2214 TNF receptor 752 CPXV- 56585 90660443 Crm-B (CrmD) GER91-210 secreted TNF- alpha- receptor- like protein Cowpox virus strain Germany 91-3 Orthopoxvirus 2214 TNF-alpha 742 CPXV- 56586 90660444 TNF-alpha- receptor (CPXV- GER91-211 receptor-like GRI-K3R) protein Cowpox virus strain Germany 91-3 Orthopoxvirus 2214 TNF receptor 642 CPXV- 56593 90660451 Crm-B (CrmB) GER91-218 secreted TNF- alpha- receptor- like protein Deerpox virus strain W-1170-84 Unclassified 1516 Secreted TNF 725 DPV- 45291 0  8 binding protein W1170_84- 008 Deerpox virus strain W-1170-84 Unclassified 1516 TNF receptor 642 DPV- 45299 0  16 (CrmB) W1170_84- 016 Deerpox virus strain W-848-83 Unclassified 1515 Secreted TNF 725 DPV- 45121 62637387  8 binding protein W848_83- 008 Deerpox virus strain W-848-83 Unclassified 1515 TNF receptor 642 DPV- 45129 62637395  16 (CrmB) W848_83- 016 Ectromelia virus strain Moscow Orthopoxvirus 1492 TNF receptor 752 ECTV-Mos- 40922 22164610  3 (CrmD) 003 Ectromelia virus strain Moscow Orthopoxvirus 1492 TNF receptor 642 ECTV-Mos- 40927 22164615  8 (CrmB) 008 Ectromelia virus strain Moscow Orthopoxvirus 1492 TNF receptor 752 ECTV-Mos- 41094 22164605 170 (CrmD) 175 Ectromelia virus strain Naval Orthopoxvirus 1499 TNF receptor 752 ECTV-Nav- 42258 0 6_177 (CrmD) 003 Ectromelia virus strain Naval Orthopoxvirus 1499 TNF receptor 642 ECTV-Nav- 42262 0  12 (CrmB) 007 Ectromelia virus strain Naval Orthopoxvirus 1499 TNF receptor 752 ECTV-Nav- 42435 0 E6 (CrmD) 180 Horsepox virus strain MNR-76 Orthopoxvirus 2230 TNF receptor 642 HSPV- 59640 1.11E+08 HSPV003 (CrmB) MNR76-003 Horsepox virus strain MNR-76 Orthopoxvirus 2230 TNF receptor 642 HSPV- 59648 1.11E+08 HSPV009 (CrmB) MNR76-011 Horsepox virus strain MNR-76 Orthopoxvirus 2230 TNF receptor 712 HSPV- 59835 1.11E+08 HSPV175 (CrmC) MNR76-198 Horsepox virus strain MNR-76 Orthopoxvirus 2230 TNF receptor 642 HSPV- 59871 1.11E+08 HSPV205 (CrmB) MNR76-234 Monkeypox Virus strain Walter Reed Orthopoxvirus 1502 TNF receptor 642 MPXV- 42873 0  2 267 (CrmB) WR267-002 Monkeypox Virus strain Walter Reed Orthopoxvirus 1502 TNF receptor 642 MPXV- 43048 0 176 267 (CrmB) WR267-177 Monkeypox virus strain COP-58 Orthopoxvirus 1520 TNF receptor 642 MPXV- 46307 59858808  2 (CrmB) COP58-002 Monkeypox virus strain COP-58 Orthopoxvirus 1520 TNF receptor 642 MPXV- 46481 59858982 176 (CrmB) COP58-176 Monkeypox virus strain Orthopoxvirus 1524 TNF receptor 642 MPXV- 47061 68448878  2 Congo_2003_358 (CrmB) COG_2003_3 58-002 Monkeypox virus strain Orthopoxvirus 1524 TNF-alpha 742 MPXV- 47251 68449068 198 Congo_2003_358 receptor (CPXV- COG_2003_3 GRI-K3R) 58-192 Monkeypox virus strain Orthopoxvirus 1524 TNF receptor 642 MPXV- 47258 68449075 205 Congo_2003_358 (CrmB) COG_2003_3 58-199 Monkeypox virus strain Orthopoxvirus 1525 TNF receptor 642 MPXV- 47261 68449282  2 Liberia_1970_184 (CrmB) LBR_1970_184- 002 Monkeypox virus strain Orthopoxvirus 1525 TNF-alpha 742 MPXV- 47450 68449471 198 Liberia_1970_184 receptor (CPXV- LBR_1970_184- GRI-K3R) 191 Monkeypox virus strain Orthopoxvirus 1525 TNF receptor 642 MPXV- 47456 68449477 205 Liberia_1970_184 (CrmB) LBR_1970_184- 197 Monkeypox virus strain Sierra Leone Orthopoxvirus 1521 TNF receptor 642 MPXV-SLE- 46484 58220472  2 (CrmB) 002 Monkeypox virus strain Sierra Leone Orthopoxvirus 1521 TNF receptor 642 MPXV-SLE- 46658 58220646 176 (CrmB) 176 Monkeypox virus strain Orthopoxvirus 1526 TNF receptor 642 MPXV- 47459 68449481  2 USA_2003_039 (CrmB) USA_2003_039- 002 Monkeypox virus strain Orthopoxvirus 1526 TNF-alpha 742 MPXV- 47648 68449670 198 USA_2003_039 receptor (CPXV- USA_2003_039- GRI-K3R) 191 Monkeypox virus strain Orthopoxvirus 1526 TNF receptor 642 MPXV- 47654 68449676 205 USA_2003_039 (CrmB) USA_2003_039- 197 Monkeypox virus strain Orthopoxvirus 1522 TNF receptor 642 MPXV- 46661 68448679  2 USA_2003_044 (CrmB) USA_2003_044- 002 Monkeypox virus strain Orthopoxvirus 1522 TNF-alpha 742 MPXV- 46850 68448868 198 USA_2003_044 receptor (CPXV- USA_2003_044- GRI-K3R) 191 Monkeypox virus strain Orthopoxvirus 1522 TNF receptor 642 MPXV- 46856 68448874 205 USA_2003_044 (CrmB) USA_2003_044- 197 Monkeypox virus strain Zaire Orthopoxvirus 1489 TNF receptor 642 MPXV-ZAR- 40363 17974915 J2L (CrmB) 002 Monkeypox virus strain Zaire Orthopoxvirus 1489 TNF-alpha 742 MPXV-ZAR- 40547 17975096 K1R receptor (CPXV- 186 GRI-K3R) Monkeypox virus strain Zaire Orthopoxvirus 1489 TNF receptor 642 MPXV-ZAR- 40554 17975103 J2R (CrmB) 193 Monkeypox virus strain Zaire_1979- Orthopoxvirus 1523 TNF receptor 642 MPXV- 46859 68449079  2 005 (CrmB) ZAR_1979_005- 002 Monkeypox virus strain Zaire_1979- Orthopoxvirus 1523 TNF-alpha 742 MPXV- 47051 68449271 198 005 receptor (CPXV- ZAR_1979_005- GRI-K3R) 194 Monkeypox virus strain Zaire_1979- Orthopoxvirus 1523 TNF receptor 642 MPXV- 47058 68449278 205 005 (CrmB) ZAR_1979_005- 201 Myxoma virus strain Lausanne Leporipoxvirus 1479 TNF receptor (M- 558 MYXV-Lau- 38428 9633794 m002L T2) 003 Myxoma virus strain Lausanne Leporipoxvirus 1479 TNF receptor (M- 558 MYXV-Lau- 38593 9633635 M_T2 T2) 169 Rabbit fibroma virus strain Kasza Leporipoxvirus 1480 TNF receptor (M- 558 SFV-Kas-002 38597 6578530 gp002L T2) Rabbit fibroma virus strain Kasza Leporipoxvirus 1480 TNF receptor (M- 558 SFV-Kas-165 38760 9633970 s002R T2) Rabbitpox virus strain Utrecht Orthopoxvirus 1494 TNF receptor 712 RPXV-Utr- 41525 44971524 161 (CrmC) 163 Swinepox virus strain Nebraska Suipoxvirus 1490 Secreted TNF 725 SWPV-Neb- 40558 18640089  3 17077-99 binding protein 003 Swinepox virus strain Nebraska Suipoxvirus 1490 Secreted TNF 725 SWPV-Neb- 40704 18640234 148 17077-99 binding protein 149 Tanapox virus strain Kenya Yatapoxvirus 3496 Secreted TNF 725 TANV-KEN- 67458 1.47E+08 2L binding protein 002 Tanapox virus strain isolate TPV- Yatapoxvirus 3497 Secreted TNF 725 TANV-COD- 67538 1.47E+08 2L RoC binding protein 002 Taterapox virus strain Dahomey Orthopoxvirus 2195 TNF receptor 642 TATV-DAH68- 52922 1.13E+08 TNF-alpha- 1968 (CrmB) 004 receptor-like protein Taterapox virus strain Dahomey Orthopoxvirus 2195 TNF receptor 642 TATV-DAH68- 52923 1.13E+08 TNF-alpha- 1968 (CrmB) 005 receptor-like protein Taterapox virus strain Dahomey Orthopoxvirus 2195 TNF receptor 642 TATV-DAH68- 53139 1.13E+08 TNF-alpha- 1968 (CrmB) 221 receptor-like protein Taterapox virus strain Dahomey Orthopoxvirus 2195 TNF receptor 642 TATV-DAH68- 53140 1.13E+08 TNF-alpha- 1968 (CrmB) 222 receptor-like protein Vaccinia virus strain 3737 Orthopoxvirus 1528 TNF receptor 642 VACV-3737- 47790 88900618 193 (CrmB) 002 Vaccinia virus strain 3737 Orthopoxvirus 1528 TNF receptor 642 VACV-3737- 47791 88900619  2 (CrmB) 003 Vaccinia virus strain 3737 Orthopoxvirus 1528 TNF receptor 712 VACV-3737- 47968 88900796 207 (CrmC) 180 Vaccinia virus strain Acambis 2000 Orthopoxvirus 2161 TNF receptor 642 VACV- 51058 38348860  2 (CrmB) Acam2000- 002 Vaccinia virus strain Acambis 2000 Orthopoxvirus 2161 TNF receptor 642 VACV- 51059 38348861  3 (CrmB) Acam2000- 003 Vaccinia virus strain Acambis 2000 Orthopoxvirus 2161 TNF receptor 712 VACV- 51244 38349046 190 (CrmC) Acam2000- 188 Vaccinia virus strain Acambis 2000 Orthopoxvirus 2161 TNF receptor 642 VACV- 51289 38349091 239 (CrmB) Acam2000- 233 Vaccinia virus strain Acambis 2000 Orthopoxvirus 2161 TNF receptor 642 VACV- 51290 38349092 240 (CrmB) Acam2000- 234 Vaccinia virus strain Acambis 3 Orthopoxvirus 2162 TNF receptor 642 VACV-Acam3- 51293 37551437  2 (CrmB) 002 Vaccinia virus strain Acambis 3 Orthopoxvirus 2162 TNF receptor 642 VACV-Acam3- 51294 37551438  3 (CrmB) 003 Vaccinia virus strain Acambis 3 Orthopoxvirus 2162 TNF receptor 712 VACV-Acam3- 51481 37551624 190 (CrmC) 190 Vaccinia virus strain Acambis 3 Orthopoxvirus 2162 TNF receptor 642 VACV-Acam3- 51518 37551661 239 (CrmB) 227 Vaccinia virus strain Acambis 3 Orthopoxvirus 2162 TNF receptor 642 VACV-Acam3- 51519 37551662 240 (CrmB) 228 Vaccinia virus strain Acambis 3000 Orthopoxvirus 1510 TNF receptor 642 VACV- 44316 47088328  2 Modified Virus Ankara (CrmB) Acam3000- 002 Vaccinia virus strain Acambis 3000 Orthopoxvirus 1510 TNF receptor 642 VACV- 44508 47088518 192 Modified Virus Ankara (CrmB) Acam3000- 194 Vaccinia virus strain Copenhagen Orthopoxvirus 1485 TNF receptor 642 VACV-Cop- 39529 335321 C22L (CrmB) 004 Vaccinia virus strain Copenhagen Orthopoxvirus 1485 TNF receptor 712 VACV-Cop- 39749 335536 A53R (CrmC) 224 Vaccinia virus strain Copenhagen Orthopoxvirus 1485 TNF receptor 712 VACV-Cop- 39750 335537 A_ORF_T (CrmC) 225 Vaccinia virus strain Copenhagen Orthopoxvirus 1485 TNF receptor 642 VACV-Cop- 39789 335576 B28R (CrmB) 264 Vaccinia virus strain DUKE Orthopoxvirus 2458 TNF receptor 642 VACV-DUKE- 63382 90819654  2 (CrmB) 002 Vaccinia virus strain DUKE Orthopoxvirus 2458 TNF receptor 642 VACV-DUKE- 63383 90819655  3 (CrmB) 003 Vaccinia virus strain DUKE Orthopoxvirus 2458 TNF receptor 712 VACV-DUKE- 63568 90819840 188 (CrmC) 188 Vaccinia virus strain DUKE Orthopoxvirus 2458 TNF receptor 642 VACV-DUKE- 63603 90819875 223 (CrmB) 223 Vaccinia virus strain DUKE Orthopoxvirus 2458 TNF receptor 642 VACV-DUKE- 63604 90819876 224 (CrmB) 224 Vaccinia virus strain LC16m8 Orthopoxvirus 1517 TNF receptor 642 VACV- 45457 56713345 m8LTR09L (CrmB) LC16m8-004 Vaccinia virus strain LC16m8 Orthopoxvirus 1517 TNF receptor 642 VACV- 45458 56713346 m8LTR08L (CrmB) LC16m8-005 Vaccinia virus strain LC16m8 Orthopoxvirus 1517 TNF receptor 712 VACV- 45693 56713579 m8229R (CrmC) LC16m8-240 Vaccinia virus strain LC16m8 Orthopoxvirus 1517 TNF receptor 712 VACV- 45694 56713580 m8230R (CrmC) LC16m8-241 Vaccinia virus strain LC16m8 Orthopoxvirus 1517 TNF-alpha 742 VACV- 45722 56713608 m8259R receptor (CPXV- LC16m8-269 GRI-K3R) Vaccinia virus strain LC16m8 Orthopoxvirus 1517 TNF receptor 642 VACV- 45733 56713619 m8RTR08R (CrmB) LC16m8-280 Vaccinia virus strain LC16m8 Orthopoxvirus 1517 TNF receptor 642 VACV- 45734 56713620 m8RTR09R (CrmB) LC16m8-281 Vaccinia virus strain LC16mO Orthopoxvirus 1518 TNF receptor 642 VACV- 45741 56713629 mOLTR09L (CrmB) LC16mO-004 Vaccinia virus strain LC16mO Orthopoxvirus 1518 TNF receptor 642 VACV- 45742 56713630 mOLTR08L (CrmB) LC16mO-005 Vaccinia virus strain LC16mO Orthopoxvirus 1518 TNF receptor 712 VACV- 45977 56713863 mO229R (CrmC) LC16mO-240 Vaccinia virus strain LC16mO Orthopoxvirus 1518 TNF receptor 712 VACV- 45978 56713864 mO230R (CrmC) LC16mO-241 Vaccinia virus strain LC16mO Orthopoxvirus 1518 TNF-alpha 742 VACV- 46006 56713892 mO259R receptor (CPXV- LC16mO-269 GRI-K3R) Vaccinia virus strain LC16mO Orthopoxvirus 1518 TNF receptor 642 VACV- 46017 56713903 mORTR08R (CrmB) LC16mO-280 Vaccinia virus strain LC16mO Orthopoxvirus 1518 TNF receptor 642 VACV- 46018 56713904 mORTR09R (CrmB) LC16mO-281 Vaccinia virus strain Lister Orthopoxvirus 1519 TNF receptor 642 VACV-Lister- 46025 0 m8LTR09L (CrmB) 004 Vaccinia virus strain Lister Orthopoxvirus 1519 TNF receptor 642 VACV-Lister- 46026 0 m8LTR08L (CrmB) 005 Vaccinia virus strain Lister Orthopoxvirus 1519 TNF receptor 712 VACV-Lister- 46261 0 m8229R (CrmC) 240 Vaccinia virus strain Lister Orthopoxvirus 1519 TNF receptor 712 VACV-Lister- 46262 0 m8230R (CrmC) 241 Vaccinia virus strain Lister Orthopoxvirus 1519 TNF-alpha 742 VACV-Lister- 46290 0 m8259R receptor (CPXV- 269 GRI-K3R) Vaccinia virus strain Lister Orthopoxvirus 1519 TNF receptor 642 VACV-Lister- 46301 0 m8RTR08R (CrmB) 280 Vaccinia virus strain Lister Orthopoxvirus 1519 TNF receptor 642 VACV-Lister- 46302 0 m8RTR09R (CrmB) 281 Vaccinia virus strain Orthopoxvirus 2659 TNF receptor 642 VACV- 64335 0 List002* Lister_VACV107 (CrmB) Lister_VACV107- 002 Vaccinia virus strain Orthopoxvirus 2659 TNF receptor 712 VACV- 64509 88854255 List172 Lister_VACV107 (CrmC) Lister_VACV107- 176 Vaccinia virus strain Orthopoxvirus 2659 TNF-alpha 742 VACV- 64532 88854282 List195 Lister_VACV107 receptor (CPXV- Lister_VACV107- GRI-K3R) 199 Vaccinia virus strain Orthopoxvirus 2659 TNF receptor 642 VACV- 64537 0 List200* Lister_VACV107 (CrmB) Lister_VACV107- 204 Vaccinia virus strain MVA-I721 Orthopoxvirus 2696 TNF receptor 642 VACV- 65270 0 192 (CrmB) MVA_I721- 056 Vaccinia virus strain MVA-I721 Orthopoxvirus 2696 TNF receptor 642 VACV- 65328 0  2 (CrmB) MVA_I721- 114 Vaccinia virus strain Western Orthopoxvirus 1500 TNF receptor 642 VACV-WR- 42439 66275799  2 Reserve (CrmB) 002 Vaccinia virus strain Western Orthopoxvirus 1500 TNF receptor 642 VACV-WR- 42441 66275801  4 Reserve (CrmB) 004 Vaccinia virus strain Western Orthopoxvirus 1500 TNF receptor 712 VACV-WR- 42618 66275976 179 Reserve (CrmC) 179 Vaccinia virus strain Western Orthopoxvirus 1500 TNF receptor 642 VACV-WR- 42654 66276012 215 Reserve (CrmB) 215 Vaccinia virus strain Western Orthopoxvirus 1500 TNF receptor 642 VACV-WR- 42656 66276014 217 Reserve (CrmB) 217 Variola major virus strain Orthopoxvirus 1481 TNF receptor 642 VARV- 38952 439102 G2R Bangladesh 1975 (CrmB) BGD75maj- 191 Variola minor virus strain Garcia Orthopoxvirus 1482 TNF receptor 642 VARV- 39160 5830759 G2R 1966 (CrmB) Gar_1966- 207 Variola virus strain Afghanistan 1970 Orthopoxvirus 2197 TNF receptor 642 VARV-AFG70- 53546 1.1E+08 Crm-B Variolator 4 (CrmB) 202 secreted TNF- alpha- receptor- like protein Variola virus strain Bangladesh 1974 Orthopoxvirus 2216 TNF receptor 642 VARV- 56989 94484853 Crm-B (Shahzaman) (CrmB) BGD74_shz- secreted TNF- 197 alpha- receptor- like protein Variola virus strain Bangladesh 1974 Orthopoxvirus 2217 TNF receptor 642 VARV- 57187 94485051 Crm-B (Solaiman) (CrmB) BGD74_sol- secreted TNF- 197 alpha- receptor- like protein Variola virus strain Bangladesh 1974 Orthopoxvirus 2215 TNF receptor 642 VARV- 56791 94484655 Crm-B (nur islam) (CrmB) BGD74_nur- secreted TNF- 197 alpha- receptor- like protein Variola virus strain Bangladesh 1975 Orthopoxvirus 2198 TNF receptor 642 VARV- 53747 1.1E+08 Crm-B v75-550 Banu (CrmB) BGD75_Banu- secreted TNF- 200 alpha- receptor- like protein Variola virus strain Benin, Dahomey Orthopoxvirus 2224 TNF receptor 642 VARV-BEN68- 58617 94483844 Crm-B 1968 (v68-59) (CrmB) 207 secreted TNF- alpha- receptor- like protein Variola virus strain Botswana 1972 Orthopoxvirus 2225 TNF receptor 642 VARV- 58820 94484048 Crm-B (v72-143) (CrmB) BWA72-201 secreted TNF- alpha- receptor- like protein Variola virus strain Botswana 1973 Orthopoxvirus 2226 TNF receptor 642 VARV- 59022 94484250 Crm-B (v73-225) (CrmB) BWA73-201 secreted TNF- alpha- receptor- like protein Variola virus strain Brazil 1966 (v66- Orthopoxvirus 2227 TNF receptor 642 VARV-BRA66- 59232 94484457 Crm-B 39 Sao Paulo) (CrmB) 209 secreted TNF- alpha- receptor- like protein Variola virus strain China Horn 1948 Orthopoxvirus 2203 TNF receptor 642 VARV- 54363 1.1E+08 Crm-B Sabin Lab July 1948 (CrmB) CHN48-203 secreted TNF- alpha- receptor- like protein Variola virus strain Congo 1970 v70- Orthopoxvirus 2229 TNF receptor 642 VARV- 59636 1.1E+08 Crm-B 46 Kinshasa (CrmB) COG70_46- secreted TNF- 201 alpha- receptor- like protein Variola virus strain Congo 9 1970 Orthopoxvirus 2228 TNF receptor 642 VARV- 59434 94485252 Crm-B (v74-227 Gispen) (CrmB) COG70_227- secreted TNF- 200 alpha-receptor- like protein Variola virus strain Ethiopia 1972 Orthopoxvirus 2231 TNF receptor 642 VARV- 60075 94485455 Crm-B (Eth16 R14-1X-72 Addis) (CrmB) ETH72_16- secreted TNF- 202 alpha- receptor- like protein Variola virus strain Ethiopia 1972 Orthopoxvirus 2232 TNF receptor 642 VARV- 60276 94485657 Crm-B (Eth17 R14-1X-72 Addis) (CrmB) ETH72_17- secreted TNF- 200 alpha- receptor- like protein Variola virus strain Germany 1958 Orthopoxvirus 2233 TNF receptor 642 VARV- 60477 1.1E+08 Crm-B Heidelberg (CrmB) DEU58-200 secreted TNF- alpha- receptor- like protein Variola virus strain Guinea 1969 Orthopoxvirus 2234 TNF receptor 642 VARV-GIN69- 60683 94485860 Crm-B (005) (CrmB) 205 secreted TNF- alpha- receptor- like protein Variola virus strain India 1953 (Kali- Orthopoxvirus 2238 TNF receptor 642 VARV- 61490 94486063 Crm-B Muthu-M50 Madras) (CrmB) IND53_mad- secreted TNF- 200 alpha- receptor- like protein Variola virus strain India 1953 (New Orthopoxvirus 2239 TNF receptor 642 VARV- 61691 94486265 Crm-B Delhi) (CrmB) IND53_ndel- secreted TNF- 200 alpha- receptor- like protein Variola virus strain India 1964 7124 Orthopoxvirus 2240 TNF receptor 642 VARV- 61897 1.1E+08 Crm-B Vellore (CrmB) IND64_vel4- secreted TNF- 204 alpha- receptor- like protein Variola virus strain India 1964 7125 Orthopoxvirus 2241 TNF receptor 642 VARV- 62100 1.1E+08 Crm-B Vellore (CrmB) IND64_vel5- secreted TNF- 202 alpha- receptor- like protein Variola virus strain India 3 Major Orthopoxvirus 1483 TNF receptor 642 VARV- 39361 9627717 G4R 1967 (CrmB) IND3_1967- 199 Variola virus strain Iran 1972 2602 Orthopoxvirus 2235 TNF receptor 642 VARV-IRN72- 60887 1.1E+08 Crm-B Tabriz (CrmB) 202 secreted TNF- alpha- receptor- like protein Variola virus strain Japan 1946 Orthopoxvirus 2243 TNF receptor 642 VARV- 62475 94486468 Crm-B (Yamada MS-2(A) Tokyo) (CrmB) JPN46_yam- secreted TNF- 200 alpha- receptor- like protein Variola virus strain Japan 1951 Orthopoxvirus 2244 TNF receptor 642 VARV- 62676 94486670 Crm-B (Harper, Masterseed) (CrmB) JPN51_hrpr- secreted TNF- 199 alpha- receptor- like protein Variola virus strain Japan 1951 Orthopoxvirus 2245 TNF receptor 642 VARV- 62878 94486872 Crm-B (Stillwell, Masterseed) (CrmB) JPN51_stwl- secreted TNF- 200 alpha- receptor- like protein Variola virus strain Korea 1947 (Lee, Orthopoxvirus 2236 TNF receptor 642 VARV- 61089 94487076 Crm-B Masterseed) (CrmB) KOR47-201 secreted TNF- alpha- receptor- like protein Variola virus strain Kuwait 1967 Orthopoxvirus 2237 TNF receptor 642 VARV- 61289 94487276 Crm-B (K1629) (CrmB) KWT67-199 secreted TNF- alpha- receptor- like protein Variola virus strain Nepal 1973 V73- Orthopoxvirus 2221 TNF receptor 642 VARV-NPL73- 57991 1.1E+08 Crm-B 175 (CrmB) 201 secreted TNF- alpha- receptor- like protein Variola virus strain Niger 1969 (001, Orthopoxvirus 2222 TNF receptor 642 VARV- 58200 94487481 Crm-B importation from Nigeria) (CrmB) NER69-207 secreted TNF- alpha- receptor- like protein Variola virus strain Sierra Leone Orthopoxvirus 2223 TNF receptor 642 VARV-SLE68- 58408 94488089 Crm-B 1969 (V68-258) (CrmB) 206 secreted TNF- alpha- receptor- like protein Variola virus strain Somalia 1977 Orthopoxvirus 2218 TNF receptor 642 VARV- 57387 94488290 Crm-B (V77-1252) (CrmB) SOM77_1252- secreted TNF- 199 alpha- receptor- like protein Variola virus strain Somalia 1977 Orthopoxvirus 2219 TNF receptor 642 VARV- 57587 94488490 Crm-B (V77-1605) (CrmB) SOM77_1605- secreted TNF- 199 alpha- receptor- like protein Variola virus strain Somalia 1977 Orthopoxvirus 2220 TNF receptor 642 VARV- 57789 1.1E+08 Crm-B V77-2479 (CrmB) SOM77_ali- secreted TNF- 201 alpha- receptor- like protein Variola virus strain South Africa 1965 Orthopoxvirus 2210 TNF receptor 642 VARV- 55772 94487683 Crm-B (102 Natal, Ingwavuma) (CrmB) ZAF65_102- secreted TNF- 200 alpha- receptor- like protein Variola virus strain South Africa 1965 Orthopoxvirus 2211 TNF receptor 642 VARV- 55973 94487885 Crm-B (103 Tvaal, Nelspruit) (CrmB) ZAF65_103- secreted TNF- 200 alpha- receptor- like protein Variola virus strain Sudan 1947 Orthopoxvirus 2212 TNF receptor 642 VARV- 56173 94488691 Crm-B (Juba) (CrmB) SDN47_jub- secreted TNF- 199 alpha- receptor- like protein Variola virus strain Sudan 1947 Orthopoxvirus 2213 TNF receptor 642 VARV- 56374 94488892 Crm-B (Rumbec) (CrmB) SDN47_rum- secreted TNF- 200 alpha- receptor- like protein Variola virus strain Sumatra 1970 Orthopoxvirus 2208 TNF receptor 642 VARV- 55370 1.1E+08 Crm-B V70-222 (CrmB) SUM70_222- secreted TNF- 200 alpha- receptor- like protein Variola virus strain Sumatra 1970 Orthopoxvirus 2209 TNF receptor 642 VARV- 55570 94489091 Crm-B V70-228 (CrmB) SUM70_228- secreted TNF- 198 alpha- receptor- like protein Variola virus strain Syria 1972 V72- Orthopoxvirus 2206 TNF receptor 642 VARV-SYR72- 54968 1.1E+08 Crm-B 199 (CrmB) 202 secreted TNF- alpha- receptor- like protein Variola virus strain Tanzania 1965 Orthopoxvirus 2207 TNF receptor 642 VARV-TZA65- 55169 94489291 Crm-B kembula (CrmB) 200 secreted TNF- alpha- receptor- like protein Variola virus strain United Kingdom Orthopoxvirus 2204 TNF receptor 642 VARV- 54566 94489494 Crm-B 1946 Harvey (CrmB) GBR44_harv- secreted TNF- 201 alpha- receptor- like protein Variola virus strain United Kingdom Orthopoxvirus 2205 TNF receptor 642 VARV- 54765 94489693 Crm-B 1946 Hinden (Middlesex) (CrmB) GBR46_hind- secreted TNF- 198 alpha- receptor- like protein Variola virus strain United Kingdom Orthopoxvirus 2202 TNF receptor 642 VARV- 54159 94489894 Crm-B 1947 Higgins (Staffordshire) (CrmB) GBR47_hig- secreted TNF- 200 alpha- receptor- like protein Variola virus strain United Kingdom Orthopoxvirus 2200 TNF receptor 642 VARV- 53957 94490101 Crm-B 1952 Butler (CrmB) GBR52_but- secreted TNF- 209 alpha- receptor- like protein Variola virus strain Yugoslavia 1972 Orthopoxvirus 2196 TNF receptor 642 VARV- 53343 94490304 Crm-B V72-164 (CrmB) YUG72-200 secreted TNF- alpha- receptor- like protein Yaba monkey tumor virus strain Yatapoxvirus 1503 Secreted TNF 725 YMTV- 43051 38229171 2L Amano binding protein Amano-002 Yaba-like Disease Virus strain Davis Yatapoxvirus 1487 Secreted TNF 725 YLDV-Davis- 40051 12084985 2L binding protein 002

While certain of the preferred embodiments of the present invention have been described and specifically exemplified above, it is not intended that the invention be limited to such embodiments. Various modifications may be made thereto without departing from the scope and spirit of the present invention, as set forth in the following claims. 

What is claimed is:
 1. A pharmaceutical composition comprising a humanized isolated antibody or functional fragment thereof immunologically specific for a viral interferon α/β binding protein, contained in a pharmaceutically acceptable carrier suitable for passive immunization into a human subject, said antibody cross reacting with and blocking the activity of an interferon α/β binding protein from a pox virus selected from the group consisting of monkey pox virus (MPXV), variola virus (VARV) and ectromelia virus (ECTV).
 2. A method for passively immunizing a subject against pox infection comprising administering an effective amount of the composition of claim 1 to a subject in need thereof, said administration being effective to treat or attenuate said pox infection.
 3. The method of claim 2, wherein said pox infection is selected from the group consisting of small pox infection and monkey pox infection, said method optionally comprising administration of an anti-viral agent. 